1985 — 1998 |
Lee, Virginia M |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Regulation of Neurofilament Phosphorylation &Expression @ University of Pennsylvania
The long-term objective of this research program is to determine the function(s) of neurofilaments (NFs). NFs, the-major cytoskeletal structures large axons, are comprised of a triplet of proteins each of which contains a core region and a peripheral or COOH terminal domain of varying length. The latter is highly extended in the two larger NF subunits (NF-H and NF-M). Since the peripheral extensions of NF-H and NF-M contain multiple phosphorylation sites, including at least one multi-phosphorylation repeat, the phosphorylation of the peripheral domains of NF-H and NF-M is speculated to mediate important functions subserved by NFs putative functions ascribed to axonal NFs include: the regulation of fiber caliber, the interactions of NFs with one another and with other axonal organelles, the determination of the impulse conducting properties of axons that are thought to depend on the diameter of a given axon. For these reasons, this renewal application will: 1) define all potential phosphorylation sites on NF-M and NF-H; 2) identify kinases that phosphorylate NF-M and NF-H at physiological sites; 3) determine how these kinases modulate phosphorylation at these sites; 4) investigate the role of phosphorylation in the regulation of the diameter of axons. This research program will contribute new insights into those NF functions that are mediated by the differential phosphorylation of NFs. Further, the information obtained from these studies is likely to contribute towards a better understanding of the role that aberrant phosphorylation of neuronal cytoskeletal proteins may play in the pathogenesis of different neurodengenerative diseases such as Alzheimer's disease.
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0.936 |
1992 — 2001 |
Lee, Virginia M |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Biology of Alzheimer Paired Helical Filaments @ University of Pennsylvania |
0.936 |
1993 — 1997 |
Lee, Virginia M |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
In Vitro and in Vivo Models of Alzheimer's Disease @ University of Pennsylvania
Beta-amyloid deposits and neurofibrillary tangles (NFTs) are signature lesions of Alzheimer's disease (AD), but the significance of these lesions is enigmatic. The deposition of Beta-amyloid or A4 peptides (BetaA4) in the AD brain may reflect deranged processing of 1 or more of 3 major CNS amyloid precursor proteins (APPs), and neurons ar a potential source of BetaA4 in AD. To understand the role of human CNS neurons in BetaA4 deposition, it is critical to develop in vitro and in vivo models of normal and aberrant APP metabolism in CNS neurons. New procedures to obtain >99% pure human neurons (NT2N cells) that secrete abundant BetaA4 following treatment of a human teratocarcinoma cell line (Ntera2 or NT2 cells) with retinoic acid now allow studies of APP metabolism and the generation of BetaA4 in human CNS neurons. Since grafts of NT2N cells survive in rodent brains for >1 year, APP biology can be studied in human neurons in an in vivo CNS environment. Finally, injections into rat brains of abnormal tau (i.e. A68) from paired helical filaments (PHFs) in AD NFTs result in co- deposits of BetaA4/A68 interactions in vivo. To accomplish the goals of this Program Project, an Administrative and a Neuroscience Core facilitate the research of 4 Projects. Project 1 studies the biosynthesis, processing, intracellular transport and recycling of APPs as well as the site(s) at which BetaA4 is generated in neurons and secreted using wild type and transfected NT2/NT2N cells. Project 2 characterizes APP glycoforms from AD and control brains and determines the role of glycosylation in APP metabolism and in the production of BetaA4 in NT2/NT2N cells and in glycosylation deficient non-neuronal cells transfected with APP CDNAS. Project 3 examines interactions of APPs with the neuronal cytoskeleton in NT2/NT2N cells and assesses effects of perturbations of the neuronal cytoskeleton on APP metabolism and BetaA4 production. Finally, Project 4 models BetaA4 pathology by grafting NT2N cells, or by injecting NFT components (e.g. A68 derived from AD brains) into the CNS of rodents. In sum, this Program Project will develop a more precise understanding of APP metabolism and mechanisms leading to the production of BetaA4 in human neurons, delineate critical metabolic events that lead to the deposition of BetaA4 in the AD brain and establish in vitro and in vivo models of AD amyloidosis.
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0.936 |
1995 — 2002 |
Lee, Virginia M |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
In Vitro and in Vivo Models of Alzheimers Disease @ University of Pennsylvania
The competing renewal of this Program Project builds on important research findings from the initial funding period that advanced understanding of the intra-neuronal processing of the amyloid precursor proteins (APP) to generate alphabeta peptides, including a formic acid soluble pool of Abeta, and the role of human neuron derived alpha beta in the induction of neuron degeneration of and other pathologies found in the Alzheimer's disease (AD) brain. Based on their data, the investigators in the competing renewal application view the accumulation of extracellular Abeta deposits as necessary, but not sufficient to induce neurons to degenerate in AD. Provocative data on the intra-neuronal generation of amyloidogenic Abeta1-42 in vitro in human neuron-like NT2N cells and the dramatic augmentation of neuron death by traumatic brain injury (TBI) in transgenic mice prior to the formation of Alphabeta deposits in these mice are reported here, and this has led the investigators to propose a novel "two hit" hypothesis to explain how Abeta could compromise the viability of neurons in AD. Specifically, they propose that neurons have a latent vulnerability to the toxic effects of high concentrations of amyloidogenic alphabeta (the "first hit"), but this vulnerability only becomes manifest when these neurons are subjected to a second perturbation (i.e. the "second hit") such as TBI or cellular stress. Moreover, based on studies from the previous funding period of this Program Project, it is reasonable to consider the intra-neuronal milieu as the site wherein the "first hit" initially occurs. To test this hypothesis, the investigators use complementary research strategies to pursue 4 separate Projects: 1) "Biosynthesis And Processing Of Abeta In NT2N Cells" (R.W. Doms); 2) "Regulation of Intra-neuronal Abeta In Vitro" (V.M.-Y. Lee); 3) "Signal Transduction of APP Secretion in NT2N Cells" (B.A. Wolf); 4) "Traumatic Brain Injury and Alzheimer's Disease" (J.Q. Trojanowski). With the support of an Administrative and a Neuroscience Core, the investigators of this Program Project will determine how the insidious, age-dependent accumulation of intra-neuronal Abeta ("first hit") becomes toxic to selectively vulnerable neurons following the exposure of these neurons to another insult (i.e. the "second hit"), and the accomplishment of these studies is expected to have implications of understanding and treating AD.
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0.936 |
1996 — 2002 |
Lee, Virginia M |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Phosphatases in Neurofibrillary Degeneration @ University of Pennsylvania
Abstract: Recent studies of biopsy derived normal adult human tau indicate that these proteins are phosphorylated at nearly all of the sites previously identified as "abnormal" in paired helical filament (PHF) tau (PHF-tau) in the brains of Alzheimer's disease (AD) patients with or without cortical Lewy bodies (LBs), and in the brains of Parkinson's disease (PD) patients who become demented and show postmortem evidence of PD and AD (PD/AD). Thus, neurofibrillary tangles (NFTs) and related lesions composed of PHF-tau are characteristic of AD with or without an associated LB disorder. In contrast to PHF-tau, biopsy derived normal human tau can be induced at room temperature to undergo rapid and selective dephosphorylation at many of the so-called "abnormal" sites that are retained in PHF-tau. These provocative observations mandate a re-assessment of prevailing views about the pathogenesis of PHF-tau, and they imply that previously described differences in the phosphorylation sites and/or state of autopsy derived normal human tau versus PHF-tau reflect the differential activities of phosphatases in the postmortem control versus AD brain. Indeed, protein phosphatase 2A (PP2A) has been implicated in the failure of PHF-tau to undergo efficient dephosphorylation, and the down-regulation of PP2A could lead to the accumulation of PHF-tau in neurofibrillary lesions in AD, the LB variant of AD (LBVAD) and PD/AD. Since heterotrimeric (i.e. A, B and C subunits) but not heterotrimeric (i.e. A and C subunit) PP2A effectively dephosphorylates tau, alterations in the accessory, catalytic and regulatory subunits of PP2A could play a central role in the generation of PHF-tau. To pursue this hypothesis, this project will: 1.) Compare the sites and extent of phosphorylation in PHF-tau and biopsy derived normal human tau; 2.) Develop antibodies to each subunit heterotrimeric PP2A, and localize them in the brains of controls and patients with AD, the LBVAD and PD/AD; 3) Compare levels of heterotrimeric and heterotrimeric PP2A in the same group of brains; 4.) Characterize the repertoire of PP2A subunits in human biopsy brain samples; 5.) Assess changes in the mRNA levels of PP2A subunits in normal neurons and adjacent tangle bearing neurons in the brains of patients with AD, the LBVAD and PD/AD. These studies will provide important insights into the role of phosphatases in the pathogenesis of PHF-tau in AD and PD/AD.
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0.936 |
1997 — 2017 |
Lee, Virginia M |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Training in Age Related Neurodegenerative Diseases @ University of Pennsylvania
DESCRIPTION (provided by applicant): This application represents the third competitive renewal for our Training Program that prepares young investigators to conduct research in age-related neurodegenerative diseases. Through an intensive program of education, research training, and mentorship, these trainees will become independent investigators who will pursue careers to further our understanding of the etiology, pathogenesis, diagnosis, and treatment of these diseases. Trainees will include predoctoral PhD and MD/PhD students in neuroscience and related disciplines as well as postdoctoral PhD and MD scientists with prior training in the neurosciences, pharmacology, neuropathology, psychiatry, and gerontology. Predoctoral trainees will be given a solid background in neuroscience and related disciplines, including exposure to many diverse techniques, methods, and approaches in the setting of a research intensive academic medical center and university with a highly interactive group of trainers. They will then select a mentor from a pool of seventeen trainers with wide-ranging interests and complementary expertise. Postdoctoral trainees will participate actively in investigations underway in the laboratory of their choosing. Joint supervision of a trainee by more than one trainer will be encouraged; and physician trainees will also have the opportunity to pursue patient oriented research. Penn has an extensive didactive program in neurosciences, pharmacology, and other basic sciences that can be individually tailored to the needs of each trainee as a supplement to their core research training. Each trainee will undertake an independent project that will provide experience in the design and analysis of experiments and in the presentation and publication of results. Trainees will also participate in weekly research seminars that promote a constant interchange among trainees and trainers and encourage collaboration.
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0.936 |
1998 — 2009 |
Lee, Virginia M |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Core--Neuroscience @ University of Pennsylvania
Core B, the Neuroscience Core, is designed to facilitate the research conducted in each of the Projects of this Program Project grant by providing assistance and support for a number of 'core' activities that are common to Projects 1-4. Since all 4 Projects will require antibodies as essential tools for the proposed studies, a major activity will be the generation, characterization and provision of antibody probes to all investigators in this Program Project. A second core activity which is also essential to the success of Projects 1-4 is the provision of all reagents for the precise measurements of Abeta/1-40 and Abeta/1-42 in a sandwich ELISA. Since Projects 1-3 will use pure NT2N neurons for almost of the proposed studies, the Neuroscience Core will generate greater than 99% pure NT2N neurons in large quantities to supplement those generated by the individual labs. Core B will provide reagents and assistance for the use of Semliki Forest virus (SFV) vectors, and will also develop bicistronic SFV vectors for the expression of 2 different transgenes in NT2N cells. Finally, Core B will develop lentiviral vectors for stable and long-term expression of transgenes in post-mitotic NT2N neurons and in brains of experimental animals. In summary, by providing for several essential scientific needs of all of the Projects in this Program Project, the Neuroscience Core will play a vital role in contributing to the successful accomplishment of the research goals of this Program Project.
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0.936 |
1998 — 2002 |
Lee, Virginia M |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Regulation of Intraneuronal Ab in Vitro @ University of Pennsylvania
Alzheimer's disease (AD) is characterized by hallmark lesions such as amyloid rich senile plaques and neurofibrillary tangles. Amyloid beta (Abeta) peptides, which are derived from the proteolytic processing of one or more of the alternatively spliced Abeta precursor protein (APP) isoforms are the building blocks of the amyloid fibrils in the neuritic plaques that accumulate in the brains of patients with AD. The 2 major forms of Abeta in amyloid plaques terminate at amino acid 40 or 42/43 of this peptide, and brain cells secrete much high levels of Abeta/1-40 than Abeta/1-42. However, Abeta/1-42 is much less soluble than it aggregates far more readily than Abeta/1-40. Indeed, Abeta/1-42 predominates in the amyloid plaques that riddle the AD brain. Thus, the elucidation of intracellular pathways that lead to the production of Abeta particularly Abeta/1-42 in brain cells such as the neuron would increase our understanding of those mechanisms that underlie the pathogenesis of senile plaques in AD. During the last funding cycle of this Project, we identified the endoplasmic reticulum/intermediate compartment (ER/IC) as a novel site for the production of Abeta/1-42 but not Abeta/1-40 in human NT2N neurons. Significantly, some of the ER/IC produced Abeta/1-42 formed a stable, insoluble pool of intracellular Abeta that progressively accumulated as the NT2N neurons aged in culture. This aggregated intracellular Abeta/1-42 could compromise the survival of selectively vulnerable neurons. Thus, the studies proposed in this renewal application will test the hypothesis that perturbation of APP processing leading to progressive intracellular accumulation of Abeta particularly Abeta/1-42 in AD brains may lead to neuron death. To accomplish this, we will use reagents and tools that we have developed during the last funding cycle to dissect the different intracellular pathways that produce Abeta/1-40 and Abeta/1-42. We will determine whether or not Abeta/1-42, soluble intracellular Abeta/1-40 and Abeta/1-42 as well as insoluble, aggregated Abeta/1-40 and Abeta/1-42. Close collaboration with other investigators in the Program Project will allow us to determine how the production of the different pools of Abeta particularly intracellular Abeta/1-42 are regulated. These studies should also provide clues to the importance of intracellular Abeta in neuron death.
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0.936 |
2000 — 2009 |
Lee, Virginia M |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Biochemical and Immunohistochemical Analysis of Ftds @ University of Pennsylvania
neuropathology; neurogenetics; tau proteins; immunocytochemistry; neurofibrillary tangles; cerebral degeneration; protein binding; pathologic process; Alzheimer's disease; microtubules; gene mutation; family genetics; neural degeneration; clinical research; in situ hybridization; human subject;
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0.936 |
2000 — 2004 |
Lee, Virginia M |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Tauopathies: Genotype and Phenotype @ University of Pennsylvania
DESCRIPTION (Adapted from the application): The stimulus for this Program Project Grant (PPG) is the recent remarkable identification of >10 different pathogenic tau gene mutations in >20 distinct kindreds with autosomal dominant familial Frontotemporal Dementia (FTD) and Parkinsonism linked to chromosome 17 (FTDP-17). These landmark discoveries create bold new opportunities to elucidate cellular and molecular mechanisms of neurodegenerative diseases (tauopathies) characterized by prominent tau pathologies as well as the role of these pathologies in the progressive neuropsychiatric decline, brain degeneration and death of FTDP-17 patients, often before age 60. Significantly, insight into mechanisms of disease in FTDP-17 will clarify how brain degeneration occurs in more common tauopathies, including Alzheimer's disease (AD). Thus, this PPG capitalizes on the provocative discoveries of pathogenic tau gene mutations by pursuing multidisciplinary studies of the pathobiology of FTDP-17 and related tauopathies. The research interests of the investigators in this PPG converged prior to the discovery of the FTDP-17 mutations, and they now will work synergistically to develop an understanding of how abnormal tau gene regulation and tau protein dysfunction lead to the death of affected cells and diverse FTDP-17 phenotypes as well as seemingly sporadic FTDs. The goals of 4 projects in this PPG are to: 1. develop an understanding of the spectrum of clinical phenotypes that define sporadic FTDs, 2. identify new tau gene mutations and other abnormalities in tau gene regulation that cause FTDP-17 syndromes and sporadic FTDs, 3. elucidate how aberrant tau genes result in dysfunction (losses of normal functions, gains of toxic properties) of tau proteins and diverse tauopathies, 4. create transgenic mouse models of tauopathies and test hypotheses on mechanisms whereby tau pathologies lead to brain degeneration in tauopathies. Insights gained by this sophisticated, multidisciplinary team into the role of tau pathologies in mechanisms of brain degeneration in sporadic and familial tauopathies will hasten efforts to design better and more therapeutic interventions for these disorders, including AD, the most common tauopathy.
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0.936 |
2002 — 2012 |
Lee, Virginia M |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Training in Age-Related Neurodegenerative Diseases @ University of Pennsylvania
DESCRIPTION (provided by applicant): The proposed training program will mentor and educate young investigators to conduct research in age-related neurodegenerative diseases so that they can develop into independent investigators who will pursue careers to further our understanding of the etiology, pathogenesis, diagnosis and treatment of these diseases. The trainees are: (a) pre-doctoral Ph.D. and M.D./Ph.D. students in the Neurosciences and Pharmacological Sciences; (b) Ph.D. scientists with prior training in the neurosciences, pharmacology, psychology, molecular biology and biochemistry; and (c) physicians or veterinarians with prior training in neurology, neuropathology, psychiatry and gerontology. The trainees will be given a solid background in neuroscience and related disciplines to prepare them for a career in research on neurodegenerative diseases. This is a research training program that includes experience in many diverse techniques, methods and approaches to age-related neurodegenerative disease research in the setting of a research-intense academic medical center and university with a highly interactive group of trainers. Notably, Penn has an extensive didactic program in the neurosciences, pharmacology and other basic sciences that can be individually tailored to the needs of each trainee as a supplement to the core research training. Each trainee will undertake an independent project that will provide experience in the design and analysis of experiments, and in the presentation and publication of results. Weekly research seminars will provide constant interchange between trainees and trainers. Pre-doctoral students are enrolled in the Ph.D. program in Neuroscience, Pharmacological Sciences or Cell and Molecular Biology, and they progress through a thorough didactic graduate level program prior to undertaking a thesis project. The training program includes 19 individual trainers with complementary expertise in research on neurodegenerative diseases of the elderly. Each trainee will select a mentor/trainer and laboratory for his/her primary research project, although joint supervision of a trainee by more than one trainer is encouraged. Trainees also have free access to other trainers for advice, technical help, and collaboration. Physician trainees can also acquire training in patient-oriented research from trainers and consulting faculty with expertise in this increasingly important facet of aging research.
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0.936 |
2002 |
Lee, Virginia M |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Phf-Tau in Neurodegenerative Dieseases of Guam @ University of Pennsylvania
DESCRIPTION (provided by applicant): Neurodegenerative diseases that affect Chamorros in the Mariana Islands of the Western Pacific resemble Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic Lateral Sclerosis (ALS) elsewhere, but ALS, PD and dementia frequently co-occur in Chamorros, and this syndrome is known as Guam ALS/Parkinson dementia complex (ALS/PDC). However, unlike AD, PD and ALS in other populations, Guam ALS/PDC is characterized predominantly by abundant neurofibrillary tangles (NFTs) in central nervous system (CNS) neurons that progressively degenerate. ALS/PDC NFTs are indistinguishable from those in classic AD, but about 25% of ALS/PDC brains contain AD-like senile plaque (SP) deposits of Ab, and PD-like Lewy bodies (LBs) were detected recently with antibodies to a-synuclein (a-syn) in more ALS/PDC brains than previously recognized indicating that ALS/PDC is not a "pure" tauopathy. However, the NFTs in both ALS/PDC and classic AD are intraneuronal aggregates of paired helical filaments (PHFs) formed by hyperphosphorylated tau (PHF-tau) composed of all 6 brain tau isoforms, while tau isoforms containing 3 or 4 microtubule binding repeats predominate in the tangles found in other tauopathies. Recently, we generated transgenic mice overexpressing 3R tau and surprisingly they developed an ALS/PDC-Iike phenotype to provide the first experimental evidence that NFT-like tau inclusions play a mechanistic role in ALS/PDC. Nonetheless, we also hypothesize that SPs and LBs contribute to the progression of ALS/PDC, and that oxidative/nitrative damage plays a role in the development of NFT which in turn contributes to mechanisms of SP and LB formation in this disorder. Thus, the Specific Aims of this project will test the hypothesis that brain degeneration in ALS/PDC results from accumulations of NFTs, SPs and LBs formed by tau, Ab and a-syn, respectively, that are induced to fibrillize and/or aggregate and oxidative/nitrative stress plays an important role in this process in ALS/PDC.
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0.936 |
2003 — 2007 |
Lee, Virginia M |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
In Vitro in Vivo Models of Alzheimer's Disease @ University of Pennsylvania
DESCRIPTION (provided by applicant): The competing renewal of this Program Project grant (PPG) builds on important research conducted during the last 10 years in the development of in vitro and in vivo models of Alzheimer's Disease (AD) amyloidosis for the purpose of elucidating mechanisms leading to the regulation of amyloid beta (Abeta) pathogenesis. These studies are sharply focused on addressing a novel hypothesis that emerged from studies conducted in the previous funding cycle of this PPG to account for the neurotoxicity of Abeta. A "two hit" hypothesis is proposed which states that the "first hit" (i.e., elevation of full length Abeta) is necessary but not sufficient to induce neurodegeneration, and that a "second hit" (i.e. genetic and epigenetic factors) is required to render neurons susceptible to the toxic effects of Abeta. In addition to being plausible and compatible with our own preliminary data and the published literature on the biological effects of Abeta in vitro and in vivo, this hypothesis can be rigorously tested by accomplishing the goals of Projects 1-4 in this PPG application where so-called "second hit" events that augment Abeta toxicity could be oxidative stress, lipid peroxidation, traumatic brain injury, the involvement of other Abeta fragments in senile plaque formation, neurofibrillary tangles, Lewy bodies or other processes identified to occur in the AD brain. To test this hypothesis, the investigators use complementary research strategies to pursue four separate projects: 1) Cell Biology of Abeta Production (RW Doms); 2) Novel Abeta Fragments as Mediators of Alzheimer's Disease (V. M.-Y. Lee); 3) Lipid peroxidation and Alzheimer's disease phenotypes (D. Pratico); and 4) Traumatic Brain Injury and Alzheimer's Disease (J. Q. Trojanowski). With the support of the Administrative and Neuroscience Cores, the investigators will use a multi-disciplinary approach to work synergistically to advance understanding of mechanisms of Abeta-mediated neuron degeneration in AD at the molecular, cellular and in vivo levels. It is anticipated that information derived from this research could provide a rationale for the development of novel therapeutic interventions for AD.
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0.936 |
2005 — 2020 |
Lee, Virginia M |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Administrative Core @ University of Pennsylvania
ADMIN CORE: Project Summary/Abstract The Administrative Core of the competing renewal of this Program Project Grant (PPG) entitled ?Frontotemporal Dementias: Genotypes and Phenotypes? is Core A. This PPG was launched 15 years ago at the University of Pennsylvania and in the renewal period it will seek to advance understanding of mechanisms underlying the onset and progression of hereditary and sporadic forms of frontotemporal degeneration (FTD). These diverse clinical disorders are characterized by genetic and neuropathological heterogeneity. For example, FTD with underlying frontotemporal lobar degeneration (FTLD) due to neuronal and glial tau pathology (FTLD-Tau) account for ~45% of patients, while TDP-43 inclusions (FTLD-TDP) account for ~50% of affected individuals, and ~5% of cases have FUS lesions (FTLD-FUS) as the underlying neuropathology. Further, FTLD-Tau disorders, including corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and Pick's disease (PiD), are linked to genetic and environmental risk factors, and FTLD-Tau progression as well as heterogeneity may be driven mechanistically by the differential cell-to-cell spread of different species or strains of pathological tau. The major focus of this PPG competing renewal is on elucidating mechanisms underlying the onset, progression and heterogeneity of CBD, PSP and PiD. As the administrative unit of this PPG, Core A continues to exercise fiscal and administrative oversight of the PPG, facilitates interactions among PPG investigators to accomplish the PPG research goals, coordinates and integrates activities of the Projects/Cores, and provides mechanisms to advise PPG Core and Project Leaders on their progress towards accomplishing the mission of this PPG. This is achieved using strategies that have been very successful in this PPG during the current funding cycle. Hence, Core A provides a clearly delineated and proven administrative structure to foster and facilitate efforts by PPG investigators to elucidate mechanisms of the onset/progression and pathobiology of hereditary and sporadic FTLD-Tau disorders, especially CBD, PSP and PiD.
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0.936 |
2005 — 2009 |
Lee, Virginia M-Y |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Animal Models of Synucleinopathies @ University of Pennsylvania
Neurodegenerative disorders with prominent filamentous alpha-synuclein (alpha-syn) aggregates in CNS neurons or glia are known as synucleinopathies. Synucleinopathies characterized by neuronal alpha-syn inclusions, or Lewy bodies, include Parkinson's disease (PD) and dementia with LBs (DLB), while multiple system atrophy (MSA) is characterized by numerous glial cell inclusions (GCIs) and less frequent LB-like inclusions formed by fibrillar alpha-syn. Most PD is sporadic, but mutations/duplications in the alpha-syn gene of rare kindreds cause autosomal dominant hereditary PD/DLB. Thus, filamentous alpha-syn inclusions are linked to the onset/progression of synucleinopathies. In the current funding cycle, transgenic (TG) mouse models of synucleinopathies were generated that developed neuronal and glial alpha-syn pathologies recapilulating those in DLB and MSA, respectively. We now propose to use these existing TG mice together with new TG mice we will generate to test specific hypotheses regarding toxicity of a-syn and the mechanisms of alpha-syn aggregate formation. In Aim 1, we will cross our MSA-model TG mice with glial pathology, with those TG mice expressing alpha-syn in neurons, to test the hypothesis that oligodendrocyte degeneration enhances neurodegeneration. In Aim 2, we will address the significance of dopamine interactions with alpha-syn. Since all TG mice reported to express alpha-syn in neurons do not develop inclusions in dopaminergic substantia nigra (SN) neurons, we hypothesize this is due to dopamine mediated inhibition of alpha-syn fibrillization through interactions with residues 125-127. Now, we propose to test this hypothesis by generating TG mice expressing alpha-syn with these residues mutagenized asking if the removal of the dopamine/alpha-syn interaction facilitates formation of SN alpha-syn neuronal inclusions. In Aims 3, 4 and 5, we will test the hypotheses that the C-terminus of alpha-syn and Ser129 phosphorylation play important roles in the pathogenesis of alpha-syn lesions and that these lesions induce neurodegeneration in TG by impairing axonal transport. Taken together, our work will lead to more informative models of synucleinopathies and address important questions on mechanisms leading to alpha-syn pathologies and their contribution to brain degeneration in synucleinopathies.
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0.936 |
2005 — 2021 |
Lee, Virginia M |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Frontotemporal Dementias: Genotypes and Phenotypes @ University of Pennsylvania
DESCRIPTION (provided by applicant): The major goal of this Program Project Grant (PPG) is to continue to expand and further develop a vigorous research program focused on elucidating the etiology and pathogenesis of frontotemporal dementias (FTDs) tauopathies and other neurodegenerative variants of FTDs. During the last funding cycle, a close-knit and highly integrated multidisciplinary group of investigators formed a productive collaborative alliance and established a very comprehensive clinical and basic science research center-without-walls to study patients with FTDs. During the next funding period of this PPG, these seasoned investigators and young faculty newly recruited to the PPG propose a set of bold new objectives for FTD research that will be implemented through 3 Cores and 4 Projects. Specifically, they will characterize the spectrum of the clinical phenotypes seen in FTD patients, identify new mutations in FTD kindreds, elucidate mechanism of tau fibrillization, determine the building blocks ofubiquitin positive but tau, alpha-synuclein and neurofilament negative inclusions in FTD with or without motor neuron disease, and develop transgenic mouse and Co elegans models with greater versimilitude to human tau pathologies thereby leading to improvements in understanding FTDs as well as the diagnosis and treatment of these disorders.
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0.936 |
2006 |
Lee, Virginia M |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Frontotemporal Dementia: Genotype and Phenotype @ University of Pennsylvania |
0.936 |
2007 |
Lee, Virginia M |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Novel Ab Fragments as Mediators of Alzheimers Disease @ University of Pennsylvania
The deposition of amyloid beta (Abeta) peptides in senile plaques is a seminal event in the pathogenesis of Azheimer's disease (AD) and Abeta is generated from beta-amyloid precursor protein (APP) by the sequential cleavage by a recently identified beta-secretase known as BACE1 (beta-site APP cleavage enzyme 1) and the presenilin (PS) containing gamma-secretase complex. Surprisingly, BACE1 was shown to cleavage APP at both Asp 1 and Glu 11 of Abeta generating both full length Abeta1-40/42 as well as the N-terminally truncated Abeta11-40/42 peptides. However, despite the fact that Abeta11-40/42 peptides have been detected at high levels in brains of AD and Down's syndrome patients, that certain familial AD associated PS1 and APP mutations increase the deposition of the N-terminal truncated Abeta peptides and that these peptides aggregate more readily than full length Abeta peptides, the mechanism regulating the production and aggregation of Abeta11-40/42 and its role in AD pathogenesis remains unknown. In this competitive renewal application, Project 2 will test the hypothesis that Abeta11-40/42 may play a major role in increasing Abeta fibril formation, Abeta aggregation and Abeta toxicity. To accomplish our goals, we will assess and compare the distribution of Abeta11-40/42 with Abeta1-40/42 in brains of patients with mild cognitive impairment (MCI), with AD, with Down's syndrome and in control patients with no cognitive impairments (NCI). We will also compare the structure and the fibrillization properties of Abeta11-40/42 with the Abeta1-40/42 peptides. Transgenic animal models will be developed to assess the role of Abeta11-40/42 peptides in senile plaque formation, in cognitive function and in neurodegeneration. Finally we will evaluate the specific role of Abeta1-40/42 and Abeta11-40/42 oligomers in learning and memory in transgenic mouse models of AD amyloidosis. Successful completion of the proposed studies will help define the roles of Abeta11-40/42 peptides in the pathogenesis of AD.
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0.936 |
2007 — 2011 |
Lee, Virginia M |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Animal Models of Parkinson's Dementia @ University of Pennsylvania
Neurodegenerative disorders with prominent filamentous a-synuclein (a-syn) aggregates in CMS neurons or glia are known as ct-synucleinopathies or synuclienopathies, and those characterized by neuronal a-syn inclusions, or Lewy bodies (LBs) and neurites (LNs) D, include Parkinson's disease without dementia (PD), PD with dementia (PDD) and dementia with LBs (DLB). Most PD is sporadic, but mutations/duplications in the a-syn gene of rare kindreds cause autosomal dominant hereditary PD and PDD/DLB. Thus, filamentous a-syn inclusions are linked to the onset/progression of synucleinopathies, and this is re-enforced by studies in which we showed that transgenic (TG) mice engineered to express human a-syn develop neuronal and glial a-syn pathologies that recapitulate their human counterparts. We now propose to test hypotheses that a-syn which accumulates as insoluble aggregates cause cognitive impairments in PDD and DLB and these deficits are augmented by the presence of tau and/or p amyloid neuropathologies. To accomplish this, we will use brain samples obtained from Core C to compare the regional distribution of a-syn, tau and Ap neuropathology in clinically well defined PD, PDD/DLB and LB variant of Alzheimer's disease patients follwed in Core B and studied by Projects 1 and 2. Since existing a-syn TG mouse models we and others generated are inadequate to evaluate the contributions of these filamentous protein lesions to cognitive impairments, new TG mouse models with regulated overexpression of wild type (WT) or mutant a-syn in forebrain neurons will be developed to specifically address this issue. Finally, the role of regulated overexpression of tau tangles and Ap plaques in enhancing cognitive decline in the new a-syn TG mouse models will be evaluated, and comparisons of these TG mice with human disease samples from Core C will be performed in Aims 1-4 to establish verisimilitude of our models to human synucleinopathies. Taken together, our work will lead to more informative models of synucleinopathies and address important questions on mechanisms leading to a-syn pathologies and their contribution to brain degeneration in synucleinopathies.
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0.936 |
2007 |
Lee, Virginia M |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Core--Neuroscience Core @ University of Pennsylvania
Core B, the Neuroscience Core, is designed to facilitate the research conducted in each of the Projects of this Program Project Grant (PPG) by providing assistance and support for a number of 'core' activities that are common to Projects 1-4. Since all 4 Projects will require antibodies as essential tools for the proposed studies, a major activity will be the generation, characterization and provision of antibody probes to all investigators in this PPGo A second core activity which is also essential to the success of Projects 1-4 is the provision of all reagents for the precise measurements of the different amyloid Beta (ABeta) fragments including Abeta1-40 and Abeta1-42 as well as ABetax-40 and ABetax-42 in several sandwich ELISAs. Since Projects 2-4 will use a variety of single transgenic (Tg) and bigenic mice overexpressing amyloid precursor protein (APP) and several other proteins for most of the proposed studies, the Neuroscience Core will perform the initial cross-breeding, genotyping and some initial characterization of the various APP Tg mice. Once characterized, breeding pairs will be provided to the investigators of Projects 2, 3 and 4 for further expansion. However, Core B will continue to maintain small cohorts of all the Tg mice such that they can supplement the different Projects as needed for the successful completion of the experiments proposed in the PPG. Core B will also continue to provide other reagents including primary cultures of rodent neurons, human NT2N neurons as well as various viral reagents for investigators of the PPG. In summary, by providing for many essential scientific needs of all of the Projects in this PPG, the Neuroscience Core will play a vital role in contributing to the successful accomplishment of the research goals of this PPG.
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0.936 |
2010 — 2014 |
Lee, Virginia M |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Tdp-43 Proteinopathies in Als-Dementia @ University of Pennsylvania
Ubiquitin positive inclusions are found in amyotrophic lateral sclerosis (ALS), a prototypic motor neuron disease and frontotemporal lobar degeneration (FTLD), the second most common dementia after Alzheimer's disease in patients <65. Recently, investigators at the University of Pennsylvania (PENN) identified TDP-43 as the disease protein ubiquitinated in both disorders. Since motor neuron disease and dementia are found in ALS and FTLD, and since the same disease protein accumulates in both disease entities, this suggests that ALS and FTLD represent the same clinicopathological spectrum of a neurodegenerative syndrome. Thus, the major goals of this Program Project Grant (PPG) is to develop a vigorous research program focused on elucidating the etiology and pathogenesis of TDP-43 proteinopathies in ALS without or with cognitive impairment or dementia (designated as ALS, ALS-Cog and ALS-FTLD, respectively) and compare them to FTLD with and without ALS. The investigators of this new PPG are a close-knit and highly integrated multidisciplinary group of PENN physicians and basic scientists who have formed a productive collaborative alliance and established a very comprehensive clinical and basic science research program at PENN to study ALS, ALS-Cog and ALS-FTLD in patients, in human postmortem tissues and in model systems. These investigators propose a set of bold objectives for ALS and FTLD research that will be implemented through 4 Cores and 3 Projects. Specifically, they will: 1) recruit ALS, ALS-Cog and ALS-FTLD patients;2) develop new algorithms to characterize the cognitive impairments and dementia in ALS patients;3) test the hypothesis that there is a tight link between language and motor systems in the representation of action verbs;4) further characterize the spectrum of TDP-43 neuropathologies in ALS, ALS-Cog and ALS-FTLD brains and compare them with FTLD with and without ALS;5) identify hyperphosphorylated residues and N-terminal cleavage sites that generate C-terminal fragments in pathological TDP-43 and determine their significance in mechanisms of TDP-43 proteinopathies;6) establish cell culture and transgenic mouse models of TDP-43;7) use these models to elucidate the pathogenic mechanisms of neurodegeneration in TDP-43;8) determine if genetic variants in TDP-43 found in patients with ALS, ALS-Cog and ALS-FTLD are disease risk factors or pathogenic disease causing mutations;These and other studies will lead to improved understanding of the cognitive impairments and dementia in ALS as well as provide insights on the diagnosis and treatment of these disorders.
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0.936 |
2011 — 2015 |
Lee, Virginia M |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Mechanisms of Pathogenesis @ University of Pennsylvania
PROJECT SUMMARY: Frontotemporal dementia (FTD) or frontotemporal lobar degeneration (FTLD) is a group of heterogeneous sporadic and familial neurodegenerative disorders. They are the second most common cause of dementia after Alzheimer's disease (AD) in patients <65 and ~50% of FTLD patients develop abundant tau pathologies in neurons and glia (FTLD-Tau). Exciting new data from Project 2 and provocative recent reports provide models to test novel hypothesis concerning mechanisms of tauopathies. The first hypothesis we test is based on our recent observations that introduction of small amounts of exogenous tau fibril seeds into tau overexpressing cells recruits endogenous tau to fibrillize into abundant tau filamentous structures seeded by the exogenously introduced tau fibrils. These results suggest a seeding mechanism of tau tangle pathogenesis whereby fibrillar tau seeds serve as a nidus for recruiting soluble tau into fibrillar aggregates that enlarge as a result. The second hypothesis we test is based on recent data that tau fibrils spread from cell-to-cell in vitro and in tau transgenic (Tg) mouse models consistent with the notion of a prion-like mechanism for the propagation and spreading of tau pathology and disease progression. Successful completion of the studies to test these hypotheses here will address fundamental disease mechanisms of FTLD-Tau, which, in conjunction with research advances from other projects in this PPG will accelerate efforts to find better therapeutic interventions for patients with diverse FTLDs.
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0.936 |
2012 — 2016 |
Lee, Virginia M |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Mechanisms of Transmission of Pathological Alpha-Synuclein in Neurons @ University of Pennsylvania
Inclusions comprised of alpha-synuclein (a-syn), i.e. Lewy bodies (LBs) and Lewy neurites (LNs), define Parkinson's disease (PD), PD with dementia (PDD), and dementia with Lewy Bodies (DLB). DLB manifests with neuropathology typical of Alzheimer's disease (AD) in addition to LBs/LNs and given that LBs/LNs are present in ~50% of AD brains, PD, PDD, DLB, and AD may represent overlapping neurodegenerative disorders. However, the precise relationship between the clinical phenotypes and each class of central nervous system (CNS) lesions as well as their pathogenic mechanisms are poorly understood. We hypothesize that the progression of DLB and that of PD to PDD result from selective vulnerability of neurons in different brain regions and the cell-to-cell transmission of distinct pathological a-syn species (strains) that differentially promote a-syn and AD pathology in a disease- and brain region-specific manner. To test this hypothesis, we developed a unique neuron-based model of LBs/ LNs to study concomitant a-syn and AD pathology. Briefly, the application of synthetic human a-syn pre-formed fibrils (PFFs) to primary neurons from non-transgenic (non-Tg) mice seeds recruitment and conversion of soluble endogenous mouse a-syn into insoluble LB/LN-like inclusions with deleterious biological and functional consequences. Notably, endogenous mouse tau also is recruited into insoluble tau aggregates in a strain-dependent manner. This model opens up exciting new opportunities for elucidating mechanisms underlying the transmission of pathological a-syn and the role of various a-syn strains in the induction of a-syn and AD pathology during the progression of PD, PDD and DLB. Biochemical, biophysical and cell biological approaches will be used to determine if and how individual synthetic a-syn strains differ in their capacity to recruit endogenous a-syn into LBs/LNs and promote AD-like tau pathology. We will also verify the presence of a-syn strains in authentic LB/LN enriched preparations generated from PD, PDD and DLB brains characterized genetically and neuropathologically through Core C from patients followed by Core B and studied in Projects 1 and II to determine selective vulnerability and a-syn strains. Thus the Aims of Project IV are to: 1) Test the hypothesis that neurons from different CNS regions are selectively vulnerable to develop either LBs/LNs alone or LBs/LNs with AD-like tau pathology and altered levels of secreted Abeta In response to treatment with distinct a-syn PFF strains; 2) Generate and characterize synthetic a-syn PFFs strains that differentially modulate the LBs/LNs and AD pathology; 3) Determine if enriched LBs/LNs fractions isolated from different regions of PD/PDD/DLB brains, will differentially seed and cross-seed the recruitment of endogenous a-syn and tau into insoluble aggregates in primary neurons, thus reflecting strain-like properties; 4) Collaborate with Project IV to identify anti-a-syn monoclonal antibodies that block a-syn transmission in neuron-based synucleinopathy models to be used for immunotherapy in a-syn Tg mice of Project IV.
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0.936 |
2016 — 2020 |
Lee, Virginia M |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Project 3: Mechanisms of Tauopathies @ University of Pennsylvania
Project 3: Mechanisms of Tauopathies Project Leader: Virginia Lee Project Summary/Abstract Frontotemporal lobar degeneration (FTLD) with tau pathology (FTLD-Tau) is a group of clinically heterogeneous neurodegenerative disorders that include progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick's disease (PiD). FTLD-Tau diseases are caused by the accumulation of distinct pathological species or strains of tau (designated PSP-Tau, CBD-Tau, PiD-Tau) and mounting evidence supports a cell-to-cell spread of pathological tau as a major mechanism of disease that could explain the progression of FTLD-Tau since Alzheimer's disease (AD), another major tauopathy demonstrated stereotypical progressive spread of AD tau pathology (AD-Tau) that correlates with progressive dementia. Moreover, Projects 3 and 4 investigators and others modeled the progressive spread of pathological tau in vitro and in vivo and demonstrated that tau pathology propagates from cell-to-cell through intercellular transfer of pathological tau which acts as ?seeds? to recruit soluble tau and corrupt it into pathological tau. Thus, Project 3 proposes to test this ?transmission? hypothesis and to elucidate the mechanisms of progressive cell-to-cell spread of pathological tau in FTLD tauopathies. Since FTLD-Tau disorders are clinically diverse, we hypothesize that misfolded PSP-Tau, CBD-Tau and PiD-Tau represent different tau strains that differ in their conformations and seeding properties. To test this ?strain? hypothesis and to determine the molecular basis for FTLD-Tau strain diversity, we will purify pathological tau from well characterized CBD, PSP and PiD brains obtained from Core D that are deeply phenotypically characterized by Cores B-D and Projects 1 & 2 and use them for in vitro serial amplification experiments to characterize the biochemical and biophysical properties of tau strains. We will extend these studies to include cell biological research conducted on primary neurons from non-transgenic (Tg) and tau Tg mice to determine the molecular mechanisms of spread and toxicity. The effects of genetic factors identified in Project 2 in modifying the transmission of different tau strains will also be evaluated. Finally, Project 3 will also collaborate with Project 4 by providing well-characterized strain specific preparations for in vivo studies to test both the misfolded tau transmission and strain hypothesis.
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0.936 |
2018 — 2021 |
Lee, Virginia M |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Training in Alzheimer?S and Age-Related Neurodegenerative Diseases @ University of Pennsylvania
PROJECT ABSTRACT This application represents the fourth competitive renewal (years 21-25) for our T32 Program ?Training in Age-related Neurodegenerative Diseases?. The program supports 6 predoctoral and 4 postdoctoral trainees per year. The program is based at the Perelman School of Medicine, School of Arts and Sciences, School of Dental Medicine at The University of Pennsylvania, and the Children?s Hospital of Philadelphia. Together, these institutions have one of the largest programs on neurodegenerative disease research in the country, with a funded base of >$20 million as determined by federal, pharmaceutical and foundation grants held by the trainers. Among the many individuals who study neurodegenerative diseases on our campus, a select group of 22 mentors are associated with this T32 program. In our program, we place specific emphasis on collaborative science and a commitment to training students and postdoctoral fellows: all trainers have published numerous papers with other trainers, 12 of the trainers share jointly funded NIH grants with other trainers, 20 of our trainees have published with 2 or more trainers, there are many joint lab meetings, and our trainers participate in extensive programmatic activities and minority-recruitment efforts. Over the past 20 years, the program has supported 36 predoctoral trainees working in 24 different laboratories. Currently, 1 is an associate professor, 6 are assistant professors of which 3 are working on age-related neurodegenerative diseases, 1 is an instructor, 2 are postdocs, and 9 are doing residency and/or research fellowships at distinguished universities such as Harvard, Penn, Washington University, Johns Hopkins, and UCSF. Two are in private practice, 2 others are managing non-profit foundations, one is an academic biostatistician, one is a freelance science writer and another is a manager of research services. Three completed their PhDs and are in the process of completing their MDs, 6 are still in training. Our training program also supported 27 postdocs over the past 20 years working in 16 different laboratories. Currently 3 are professors, 2 are associate professors, 3 are assistant professors, 1 is a research associate,1 is an instructor, 1 is a lecturer, 1 is in private practice, 4 work in the pharmaceutical industry, 1 is a senior consultant in pharmaceutical industry, 1 is a program director at NIDDK, NIH, and 5 are still in training. Many of the predoctoral and postdoctoral trainees are stepping into leadership roles?one is the Founder and CEO of Avid Radiopharmaceuticals and a senior vice-president of clinical and product development at Eli Lilly; another is the chair of Department of Neurobiology and Behavior, University of California, Irvine; and a third is the Director of a Translational Neurotrauma Research Program at the University of Arizona. Many have established their own laboratories with independent grant support from the NIH. Thus, based on these outcomes, we feel that we are training young scientists effectively, and we propose to maintain the training program at the present size.
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0.936 |
2019 — 2020 |
Lee, Virginia M |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Examining Neuronal Resilience in a Mouse Model of Sporadic Als @ University of Pennsylvania
Project Summary/Abstract Following an injury to the brain, healthy neurons that are adjacent to the damaged area can sometimes take over the functions performed by the impaired neurons. This process has been best studied after acute nerve damage, but there is evidence that compensation by surviving neurons is also happening in the early stages of neurodegenerative diseases. In amyotrophic lateral sclerosis (ALS), the fiber type grouping in muscle samples taken from patients suggests that after an initial loss of connections between motor neurons (MNs) and muscles, new nerves are able to reconnect to allow patients to maintain movement during the disease process. A second observation made at the time of autopsy is that the vast majority of patients have an accumulation of a mislocalized protein called TDP-43 in the surviving MNs. However, because these cells are inaccessible in early disease stages, the molecular mechanisms for coping with disease processes in the MNs that send out new connections to muscles are unknown. In order to determine the dynamic responses that could allow a subpopulation of MNs to cope specifically with mislocalized TDP-43 and send out new axonal connections to muscles to prevent paralysis, we developed a mouse model in which we can induce neuronal expression of mislocalized human TDP-43, called rNLS8 mice. We then showed that rNLS8 mice have certain subsets of MNs that are uniquely vulnerable to disease, and that surviving MNs can effectively take the place of these cells, even late into the disease course. In this study, we will now identify the populations of MNs responsible for the reinnervation and restoration of function of vulnerable muscles after the initial TDP-43 triggered MN loss (Aim 1), using a combination of neuronal tracing techniques, muscle physiology, and imaging at the neuromuscular junction. We will then look for the upstream contribution of the brain's immune cells, microglia, to MN plasticity and the resultant circuit changes (Aim 2) by pharmacologically eliminating microglia and selectively reintroducing microglial derived factors that have been previously shown to influence neuronal function. Finally, molecular differences between MNs that innervate the same muscle before and after TDP-43 triggered axonal dieback will be uncovered by RNA- Sequencing and the top gene targets will be validated for their effect on motor function during ALS-like disease in rNLS8 mice (Aim 3). Completion of these studies should provide valuable insights into the potential mechanisms by which subsets of MNs can tolerate a build-up of cytoplasmic TDP-43. Moreover, understanding the mechanisms of neuronal compensation could allow for the development of therapies aimed at supporting surviving cells in order to extend their natural plasticity to slow disease and maintain function in patients.
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0.936 |
2020 — 2021 |
Lee, Virginia M |
U19Activity Code Description: To support a research program of multiple projects directed toward a specific major objective, basic theme or program goal, requiring a broadly based, multidisciplinary and often long-term approach. A cooperative agreement research program generally involves the organized efforts of large groups, members of which are conducting research projects designed to elucidate the various aspects of a specific objective. Substantial Federal programmatic staff involvement is intended to assist investigators during performance of the research activities, as defined in the terms and conditions of award. The investigators have primary authorities and responsibilities to define research objectives and approaches, and to plan, conduct, analyze, and publish results, interpretations and conclusions of their studies. Each research project is usually under the leadership of an established investigator in an area representing his/her special interest and competencies. Each project supported through this mechanism should contribute to or be directly related to the common theme of the total research effort. The award can provide support for certain basic shared resources, including clinical components, which facilitate the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence. |
Project I 'Mechanisms of Pathological Asyn Transmission' @ University of Pennsylvania
PROJECT I: ?Pathological ?-Synuclein Transmission and Strains? PROJECT LEADER: VIRGINIA M.-Y. LEE Project I Summary/Abstract Project I, formerly Project III, is renumbered as Project I to improve the flow of the Projects in our re-submitted new U19 grant entitled ?Center On Alpha-synuclein Strains In Alzheimer Disease & Related Dementias? at the University of Pennsylvania (Penn) Perelman School of Medicine (PSOM) to test the transmission and strain hypotheses of a-synucleinopathies. Dementia with Lewy bodies (DLB), Parkinson's disease (PD) without and with dementia (PDD), referred to here as Lewy body (LB) disorders (LBD), all share LB and Lewy neurite (LN) intra-neuronal pathology comprised of aggregated ?-synuclein (aSyn). LBD, PDD and Alzheimer's disease (AD) with (AD+aSyn) or without LBs (AD-aSyn) are the most common aging related dementias. Moreover, LBD, AD+aSyn and multiple system atrophy (MSA), characterized by misfolded aSyn in glial cytoplasmic inclusions (GCIs), are the major neurodegenerative synucleinopathies. This diversity of clinical features and aSyn neuropathology in brains of neurodegenerative disease patients provides indirect support for the strain hypothesis wherein pathological aSyn adopts different conformations or strains that account for clinical and pathological heterogeneity between these disorders. Further, we propose the transmission hypothesis of aSyn strains to explain the variability in progression of LBD, AD+aSyn and MSA. However, both hypotheses need rigorous testing. Recently Project I and II investigators collaborated to demonstrate that intrastriatal injections of recombinant aSyn preformed fibrils (PFFs) into wildtype (WT) mice induced the templated misfolding and aggregation of endogenous aSyn that spread progressively across the striatal connectome to form PD-like LBs and LNs followed by dopaminergic (DA) neuron loss in the substantia nigra pars compacta (SNpc) and motor impairments characteristic of PD. Our key observations have been validated by many other laboratories and extended to rats and non-human primates (see preliminary non-human primate data in Project II) thereby supporting the transmission hypothesis. These confirmatory studies also showed that these novel models recapitulate LBD pathogenesis and will facilitate LBD research. We also have identified distinct aSyn strains with different conformations and biological activities through the serial in vitro propagation of synthetic aSyn PFFs generated from recombinant aSyn and we have isolated distinct human LBD, AD+aSyn and MSA aSyn strains from LBD and AD+aSyn, as well as MSA brains characterized genetically and neuropathologically by Core C from patients followed by Core B and studied clinically in Projects III and IV thereby collaboratively linking all U19 Projects and Cores. These studies defined distinct aSyn strains from AD+aSyn and LBD brains designated as aSyn-LB (LB+LN) and from MSA brains designated as aSyn-GCI. These and other preliminary data provide the framework for investigating pathogenic mechanisms of aSyn strain transmission in this new U19 Center application. To do this, we will use biochemical, biophysical and cell biological approaches to determine the molecular signatures of aSyn-LB and aSyn-GCI strains as well as identify the determinants of cell type specificities for each strain and elucidate mechanisms for templated propagation of these strains.
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