2000 — 2004 |
Paulson, Henry L |
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. |
Mechanisms of Glutamine Repeat Neurodegeneration
Spinocerebellar ataxia type 3, also known as Machado-Joseph disease (SCA3/MJD), is a dominantly inherited neurological disorder characterized by progressive difficulties with coordination and brainstem function. SCA3/MJD is one of at least eight neurodegenerative diseases now known to be caused by an expanded CAG repeat that encodes a polyglutamine domain in the disease protein. Increasing evidence indicates that expanded polygln in itself the factor that is toxic to neurons in these diseases, and that this toxicity stems from polygln s tendency to misfold and aggregate. The overall goal of the proposed studies is to determine the mechanism of neuronal death in this group of diseases. Our hypothesis is that misfolding and aggregation of the disease protein within the nucleus of the neuron is the underlying toxic event in these diseases. The proposed experiments aim to answer how misfolding and aggregation of the SCA3/MJD disease protein compromises cellular function, ultimately leading to cell death. Studies will: 1) characterize the metabolic consequences of polyglutamine misfolding and aggregation; 2) address whether aggregates are a cause or consequence of the disease process; and 3) characterize genetic and cellular factors that modify polygln aggregation and toxicity. The proposed experiments should provide insight into the common mechanism underlying an important group of inherited human diseases, and may identify potential targets for therapeutic intervention in SCA3/MJD and related neurological disorders. Moreover, because protein misfolding is now recognized to be central to many of the most common forms of neurodegenerative disease (including Alzheimer and Parkinson disease), the proposed studies may prove to be relevant more broadly to such diseases as well.
|
0.934 |
2004 — 2007 |
Paulson, Henry L |
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. |
Analysis of Fbx2 Family of Ubiquitin Ligases
DESCRIPTION (provided by applicant): Protein degradation by the ubiquitin-proteasome pathway plays an important role in the brain, yet the components regulating protein destruction in brain are poorly understood. In three complementary aims, we will determine whether F box proteins encoded by the Fbx2 gene family function as ubiquitin ligases to mediate glycoprotein quality control in neurons. In cell models, an array of molecular and biochemical approaches will be used to test whether Fbx2 regulates ubiquitin-dependent degradation of misfolded or unassembled glycoproteins, including the neurological disease proteins TorsinA and neuroserpin. The function of Fbx2 will then be further explored in vivo using a recently generated FBx2 knockout mouse model. Finally, the expression pattern and functional properties of other F box proteins encoded by the Fbx2 family will be defined. The proposed experiments are significant because they will provide insight into how neurons handle normal and abnormal glycoproteins and will increase fundamental knowledge about an important new class of ubiquitin ligases. The results may also have implications for the pathogenesis of two poorly understood neurological diseases, DYT1 dystonia and familial neuroserpin dementia.
|
0.934 |
2005 — 2006 |
Paulson, Henry L |
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. |
Rnai For Alzheimer's Disease
AD remains incurable despite recent advances suggesting therapeutic targets. This proposal will investigate RNA interference (RNAi) as a novel therapeutic approach to suppress genes central to the disease process in AD. Studies of familial AD have revealed the critical role of beta-amyloid (A-beta) production in AD pathogenesis. Both the parent protein of A-beta, amyloid precursor protein (APP), and the APP-cleaving enzyme beta-secretase, BACE1, are attractive RNAi targets in AD because they are required for A-beta production yet are not essential in mice. Building on our recent success in suppressing these two genes in vitro, we will use viral-mediated RNAi to suppress APP and BACE1 in AD mice that are transgenic for the well-studied Swedish mutation of APP (APPsw). The central hypothesis is that RNAi will prove to be an effective and selective strategy to slow, and perhaps reverse, pathogenic processes in AD. Aim 1 will test the ability of short hairpin RNA (shRNA)-expressing virus to suppress APPsw expression and A-beta accumulation in cultured neurons and the hippocampus and cortex of AD mice. Viral delivery to mice will determine whether RNAi can prevent or reverse amyloid deposition, plaque formation and other pathological hallmarks of AD. Similar studies in aim 2 will test whether viral delivery of BACE1 shRNA effectively suppresses endogenous BACE1 expression, Ab-beta production and plaque formation. Viral delivery before and after A-beta deposition in transgenic mice will address whether pathological changes can be prevented or reversed by BACE1 suppression. Because APP and BACE1 are divergent targets with distinct biological activities, the benefits and possible adverse outcomes of suppressing either gene in the context of ongoing AD pathology may differ. Thus, aim 3 will directly compare these two suppression strategies to each other and to suppression by a novel dual-shRNA virus that targets both APPsw and BACE1.
|
0.934 |
2005 |
Paulson, Henry L |
R25Activity Code Description: For support to develop and/or implement a program as it relates to a category in one or more of the areas of education, information, training, technical assistance, coordination, or evaluation. |
Course Development in Neurobiology of Disease At the University of Iowa
[unreadable] DESCRIPTION (provided by applicant): [unreadable] [unreadable] The neuroscience graduate program at the University of Iowa currently lacks a course that links neurobiological disease mechanisms to clinical features while also emphasizing areas of current and future investigation. The RFA for "Course Development in the Neurobiology of Disease" provides us at Iowa with an opportunity to address this much-needed component of neuroscience training. The timing is ideal for the development of such a course at Iowa; the neuroscience faculty, and departmental and college administrators all support this endeavor, and neuroscience is a key growth area at Iowa. The two neuroscientists directing the development and implementation of this course, Drs. Paulson and Tranel, bring to the project an ideal, complementary blend of clinical and scientific expertise. The primary objective is to create a Neurobiology of Disease course that provides training neuroscientists with a broad, thematic understanding of disease mechanisms in nervous system disorders. With the aid of an Advisory Committee, the faculty team will develop a one-semester course that educates students in fundamental features of neurological and neuropsychiatric diseases and prepares them for future research directions. The course will be arranged thematically into five major neuroscience disease groups and will be integrated into the required core curriculum for neuroscience graduate students. More than 35 neuroscience faculty at Iowa, experts in a wide range of diseases, have expressed a strong interest in participating in this course. [unreadable] [unreadable]
|
0.934 |
2005 — 2019 |
Paulson, Henry L |
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. |
Mechanisms of Polyglutamine Neurodegeneration @ University of Michigan At Ann Arbor
? DESCRIPTION (provided by applicant): This competing renewal application seeks to understand and develop treatments for Spinocerebellar Ataxia Type 3 (SCA3), also known as Machado-Joseph disease. SCA3 is one of nine inherited neurodegenerative diseases caused by CAG repeat expansions that encode abnormally long polyglutamine tracks in the disease proteins. A fatal and incurable disorder, SCA3 may be the most common polyglutamine disease in the world. Thus, the unmet needs are great for this particular disorder and for all other polyglutamine diseases. The current proposal moves from our prior exclusively mechanistic focus to a complementary set of mechanistic and translational studies. Our central hypothesis is that the mutant SCA3 disease protein, ATXN3, is toxic due to its tendency to misfold and aggregate, implying that efforts to reduce levels of this toxic protein will be an effective route o preventive therapy. Our primary objective is to identify strategies to reduce levels of this toxic disease protein so that we can achieve our long-term goal of developing effective preventive therapy for SCA3 and other polyglutamine diseases. Aim 1 will address a central, unanswered question in all polyglutamine diseases: What is the relationship between the process of polyQ disease protein misfolding and aggregation on the one hand, and the process of neuronal dysfunction and degeneration on the other hand? Aim 1 leverages newly developed knock-in mouse models of SCA3 to test the hypothesis that the aggregation propensity of mutant ATXN3 directly contributes to toxicity, driving downstream molecular events that contribute to disease pathogenesis. Aim 2 seeks to define the genes and pathways that regulate cellular levels of ATXN3 in neurons. Aim 2 builds on our recent RNAi screen to identify genes that modulate ATXN3 and on a growing understanding of how specific ATXN3 interactors influence levels of the disease protein. Druggable genes and molecular pathways identified in Aim 2 are likely to include attractive targets for therapeutic strategies to reduce levels of the disease protein in SCA3 and possibly related polyglutamine diseases. Aim 3 takes the view that a particularly effective therapeutic strategy for SCA3 and other polyglutamine diseases is to target proximal steps in the pathogenic cascade. Aim 3 will test the efficacy of broad CNS delivery of antisense oligonucleotides targeting human ATXN3 in SCA3 transgenic mice expressing the full human ATXN3 disease gene. The complementary nature of the aims, coupled with the combined mechanistic and translational emphasis, enhances the potential impact of the proposed studies.
|
0.958 |
2007 — 2009 |
Paulson, Henry L |
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. |
Rnai For Alzheimer's Disease
AD remains incurable despite recent advances suggesting therapeutic targets. This proposal will investigate RNA interference (RNAi) as a novel therapeutic approach to suppress genes central to the disease process in AD. Studies of familial AD have revealed the critical role of beta-amyloid (A-beta) production in AD pathogenesis. Both the parent protein of A-beta, amyloid precursor protein (APP), and the APP-cleaving enzyme beta-secretase, BACE1, are attractive RNAi targets in AD because they are required for A-beta production yet are not essential in mice. Building on our recent success in suppressing these two genes in vitro, we will use viral-mediated RNAi to suppress APP and BACE1 in AD mice that are transgenic for the well-studied Swedish mutation of APP (APPsw). The central hypothesis is that RNAi will prove to be an effective and selective strategy to slow, and perhaps reverse, pathogenic processes in AD. Aim 1 will test the ability of short hairpin RNA (shRNA)-expressing virus to suppress APPsw expression and A-beta accumulation in cultured neurons and the hippocampus and cortex of AD mice. Viral delivery to mice will determine whether RNAi can prevent or reverse amyloid deposition, plaque formation and other pathological hallmarks of AD. Similar studies in aim 2 will test whether viral delivery of BACE1 shRNA effectively suppresses endogenous BACE1 expression, Ab-beta production and plaque formation. Viral delivery before and after A-beta deposition in transgenic mice will address whether pathological changes can be prevented or reversed by BACE1 suppression. Because APP and BACE1 are divergent targets with distinct biological activities, the benefits and possible adverse outcomes of suppressing either gene in the context of ongoing AD pathology may differ. Thus, aim 3 will directly compare these two suppression strategies to each other and to suppression by a novel dual-shRNA virus that targets both APPsw and BACE1.
|
0.934 |
2009 — 2013 |
Paulson, Henry L |
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. |
Integrating Quality Control: Studies of Chip in Age-Related Neurodegeneration
DESCRIPTION (provided by applicant): As humans live longer, age-related neurodegenerative disorders caused by the accumulation of abnormal proteins are becoming increasingly common. In all cells, a protein quality control network (PQC) exists to "handle" such abnormal proteins arising from mutations, environmental stressors or the aging process. The selective brain vulnerability in age-related neurodegenerative disorders, however, suggests there is something unique about PQC in the brain that makes this organ particularly susceptible to misfolded proteins. Unfortunately, which PQC components are most important in the brain and how these components respond when exposed to abnormal proteins remain unknown. The studies proposed here will systematically explore changes in PQC that occur when aggregation-prone proteins are expressed in brain and will define mechanistically how a key PQC ubiquitin ligase, CHIP, handles neurodegenerative disease proteins. The underlying hypothesis is twofold: 1) PQC in the brain fails to keep pace with mounting proteotoxic stress during age-related neurodegeneration;and 2) the brain's PQC response to proteotoxic stress relies heavily on CHIP, a multifunctional protein that mediates crosstalk between chaperone- and ubiquitin-dependent pathways. In three Aims that build off the investigators'expertise in polyglutamine neurodegeneration and ubiquitin ligase biology, we will use complementary genetic and biochemical techniques to map basal and adaptive PQC changes in the aging mouse brain and in mouse models of polyglutamine neurodegenerative disease, both in the presence and absence of CHIP. Additional studies will determine the mechanisms by which CHIP ligase complexes are regulated in brain. The proposed studies will identify key PQC components that act on abnormally folded protein in the CNS and provide insights into their mechanisms of action. The results are expected to suggest targets for therapeutic strategies in a wide range of age-related neurodegenerative disorders. PUBLIC HEALTH RELEVANCE: Many common, incurable brain diseases that develop as people get older are associated with abnormal protein deposits in the brain. This proposal seeks to understand and define the "quality control" machinery inside brain cells that counteracts these abnormal proteins. Understanding this machinery may suggest routes to therapy for a large range of sporadic and hereditary neurodegenerative diseases that occur as we age.
|
0.958 |
2010 — 2011 |
Paulson, Henry L Rodriguez, Edgardo (co-PI) [⬀] |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Rna Interference as Therapy For Spinocerebellar Ataxia Type 3
DESCRIPTION (provided by applicant): Spinocerebellar Ataxia type 3 (SCA3), also known as Machado-Joseph disease, is a dominantly inherited, progressive ataxia for which there is no cure. It is one of at least nine neurodegenerative disorders caused by CAG repeats encoding polyglutamine expansions in the respective disease genes. The expansion in SCA3 confers a toxic property on the ATXN3 disease gene product, a nonessential protein known as ataxin-3. Accordingly, suppressing the expression of ATXN3 is a potentially powerful therapeutic strategy for SCA3. Using a YAC transgenic mouse model expressing the full length human ATXN3 disease gene, we propose to test the in vivo efficacy and safety of viral-mediated RNA interference (RNAi) as therapy for SCA3. Preliminary studies have optimized microRNA-like short hairpin RNAs (shRNAs) that effectively target human ATXN3. Aim 1 will test and compare the ability of recombinant adeno-associated viruses (AAV) expressing these shRNAs to suppress expression of mutant human ATXN3 in injected cerebellum of adult mice. Parallel studies in aim 1 will also assess the safety of RNAi reagents targeting ATXN3. In Aim 2, the RNAi AAVs tested and confirmed in aim 1 will be injected bilaterally in the cerebellum, the primary neuropathological target in SCA3. Long term efficacy of RNAi to suppress both ATXN3 expression and disease-related phenotypes will be assessed. Because our AAV reagents employ elements already used in human gene therapy trials, a successful anti- ATXN3 RNAi reagent that fulfills safety and efficacy measures will represent an immediate candidate for preclinical studies leading toward a human clinical trial. PUBLIC HEALTH RELEVANCE: The proposed research will test viral-mediated RNA interference as a therapeutic strategy for the neurodegenerative disease, spinocerebellar ataxia type 3, a currently untreatable, fatal disorder. Studies carried out in a mouse model of disease are anticipate to establish that RNAi may be an effective strategy in humans with the disease.
|
0.958 |
2011 — 2012 |
Paulson, Henry L |
R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
Aim 2012 Conference
DESCRIPTION (provided by applicant): Ataxia, a disabling and frequently fatal neurological disorder, is caused by a wide range of acquired and genetic insults. The Fourth Ataxia Investigators'Meeting, AIM2012, will assemble an international roster of scientific investigators to address the multi-disciplinary nature of ataxia, to define better the pathogenic basis of ataxia and to explore routes to therapy for what is largely an untreatable disease. The conference will focus on the most recent scientific advances and emerging translational approaches toward therapy, with the objective of achieving the following five goals: 1) Enhance the open exchange of information related to ataxia research;2) Stimulate collaborative research between investigators worldwide;3) Improve our understanding of human ataxic disorders;4) Establish international protocols for the common investigation and storage of data related to ataxia and its treatment;5) Provide junior investigators with an opportunity to present their work, interact with more established scientists in the field, and have an opportunity to interact with patients and support groups so that they can see the clinical impact and importance of their work. AIM2012 will represent a critical mechanism to facilitate collaboration and discussion on ataxia research and therapeutic approaches, which is of particularly great importance now that the field is entering the phase of meaningful, multi-center clinical trials both in the United States and Europe. The location of the AIM2012 meeting in San Antonio, Texas, dovetailing with the annual meeting of the largest ataxia foundation in the country, will maximize the impact of this meeting for both scientists and patients alike. PUBLIC HEALTH RELEVANCE: The AIM2012 Fourth Ataxia Investigators'Meeting (AIM2012) will focus on the most recent advances in ataxia research and therapeutic approaches for ataxic disorders. Ataxia, which is defined as the loss of motor control, can affect all aspects of human movement gait, dexterity, speech, swallowing, and eye movements, and afflicts approximately 1 in every 2,000 individuals worldwide. Emerging genetic understanding of ataxias has recently led investigators to envision common pathogenic mechanisms and possible shared therapeutic approaches. These new concepts in disease targets and therapeutic strategy demand increased communication and collaboration among scientists and clinicians so that therapies can be developed, which is a primary goal of the 4th Ataxia Investigators'Meeting. This meeting will also provide a forum for recruiting new investigators to this field of research, which is a critically important element for achieving the rapid success that appears increasingly possible for treating these diseases.
|
0.958 |
2011 — 2012 |
Paulson, Henry L |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
Development of a Knock-in Mouse Model For Spinocerebellar Ataxia Type 3
DESCRIPTION (provided by applicant): This R03 proposal seeks to develop and the first knock-in mouse model of the polyglutamine (polyQ) neurodegenerative disease, Spinocerebellar Ataxia type 3 (SCA3). SCA3 is the most common dominantly inherited ataxia in the United States and many regions of the world, and is the second most common neurodegenerative disease caused by a polyglutamine-encoding CAG repeat expansion. In SCA3 this expansion encodes an abnormally long stretch of the amino acid glutamine in the disease protein, the de- ubiquitinating enzyme (DUB) ataxin-3. Remarkably, while much has been learned about SCA3 pathogenesis, no one has yet developed a knock-in mouse model of SCA3. In other polyglutamine diseases, knock-in models have led to fundamental insights into disease mechanisms and have begun to identify potential drug therapies for specific polyglutamine diseases. The current studies will build on our recent success targeting a human CAG repeat expansion into the murine Atxn3 locus, resulting in mice that express polyQ-expanded (pathogenic) ataxin-3. The overall hypothesis is that the resultant Atxn3 (Q82) knock-in mouse will successfully model molecular features of SCA3 and shed light on disease mechanisms. Our primary goal is to fully develop and characterize this model so that it can be made available as quickly as possible to the broader research community, though we also anticipate making discoveries that contribute to a better understanding of disease mechanisms in this polyglutamine disease. This two year R03 proposal has a single aim: to complete the development and characterization of a knock-in mouse model of SCA3. A series of behavioral, immunohistochemical, molecular and neuropathological analyses will be performed in SCA3 knock-in mice. These studies will be complemented by innovative methods of analysis that take advantage of our lab's expertise in ataxin-3 and ubiquitin biochemistry, polyglutamine-specific methods, and electrophysiology. Impact: No therapies exist for SCA3, a devastating and fatal disease, and the basic disease mechanism remains poorly understood. As the most common dominantly inherited ataxia and the second most common polyglutamine disease, SCA3 lags behind other polyQ diseases in not having a knock-in model. The knock-in model characterized here will provide researchers with the first genetically precise SCA3 model, which will greatly facilitate the study of molecular mechanisms and potential therapeutic strategies. Our laboratory's expertise in the wide range of techniques employed to characterize this line, together with our knowledge of newly recognized properties of the SCA3 disease protein, ataxin-3, also place us in an excellent position to mine this novel model for significant clues to SCA3 disease pathogenesis. PUBLIC HEALTH RELEVANCE: The studies proposed here will generate and characterize the first knock-in mouse model of the polyglutamine (polyQ) neurodegenerative disease, Spinocerebellar ataxia (SCA3). They will provide researchers with a genetically and physiologically precise SCA3 model in which to investigate disease mechanisms and test therapeutic strategies.
|
0.958 |
2015 — 2016 |
Paulson, Henry L Sharkey, Lisa Marie (co-PI) [⬀] |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Investigating Mechanisms of Ubqln2-Mediated Neurodegenerative Disease
? DESCRIPTION (provided by applicant): Ubiquilin2 (UBQLN2) is one of a family of closely related ubiquilin proteins recently implicated in a wide range of neurodegenerative diseases including Alzheimer's disease, Lewy Body Dementia, Frontotemporal Dementia and Huntington's Disease. Mutations in the UBQLN2 gene also directly cause an inherited fatal neurodegenerative disorder that spans the Frontotemporal Dementia/Amyotrophic Lateral Sclerosis (FTD/ALS) spectrum and is associated with accumulation of the RNA binding protein TDP43. The involvement of ubiquilins in numerous degenerative brain diseases reflects the fact that these proteins are believed to normally help maintain neuronal protein homeostasis, but their function in health and disease is still poorly understood. The objective of the current proposal is to leverage a valuable new research tool -- transgenic mouse lines expressing wild type or pathogenic (mutant) UBQLN2 -- to advance scientific understanding of the role of ubiquilins in a wide variety of neurodegenerative diseases, ranging from common synucleinopathies, amyloidopathies, and TDP43 proteinopathies to rarer diseases such as UBQLN2-mediated FTD/ALS. These new models are expected to accelerate discoveries about both the normal role of UBQLN2 in neurodegenerative proteinopathies and the mechanism by which mutations in this quality control protein cause FTD/ALS. The proposal has two aims that build on newly generated transgenic mouse lines, preliminary results showing robust aggregate pathology selectively in mutant UBQLN2-expressing mice, and a screen for interacting proteins that suggests UBQLN2 forms complexes with two closely related ubiquilins, UBQLN1 and UBQLN4. The first aim will seek to define the neuropathological features in transgenic mice expressing wild type or mutant UBQLN2. The second aim will assess motor, behavioral and electrophysiological changes in wild type and mutant UBQLN2 transgenic mice. The studies proposed here are expected to answer fundamental questions about normal and mutant UQBLN2 behavior and, more broadly, about the role of ubiquilins in brain health and disease, that could have important ramifications for therapeutic strategies.
|
0.958 |
2016 — 2020 |
Ivanova, Magdalena Paulson, Henry L |
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. |
Integrating Quality Control: Studies of Ubqln2 in Age-Related Neurodegeneration
? DESCRIPTION (provided by applicant): Mutations in Ubiquilin2 (UBQLN2) were recently identified as a cause of Frontotemporal Dementia and Amyotrophic Lateral Sclerosis (FTD/ALS) associated with TDP43 deposition, and UBQLN2 itself has emerged as a sensitive marker of pathology in a substantial portion of sporadic and familial FTD/ALS. UBQLN2 is also one of four closely related ubiquilins, a family of ubiquitin adaptor proteins implicated in ubiquitin-dependen protein quality control in the nervous system. Although mounting evidence implicates UBQLN2 and other ubiquilins in numerous age-related neurodegenerative diseases defined by protein accumulation, their functions in brain health and disease remain poorly understood. Moreover, the mechanisms by which mutations in UBQLN2 cause FTD/ALS are unknown. The current proposal investigates these critical gaps in knowledge. Our primary goals are to define pathogenic mechanisms in UBQLN2-mediated FTD/ALS and to gain insight into the cellular pathways driving TDP43 deposition and neurodegeneration in FTD/ALS. In three specific aims employing complementary approaches (biochemistry, animal models, and automated microscopy), our investigative team will seek to 1) define the molecular properties driving aggregation of mutant UBQLN2, 2) explore the functional consequences of UBQLN2 aggregation in mouse models, and 3) investigate how mutant UBQLN2 alters TDP43 homeostasis in neurons. The proposed studies build on: novel biochemical insights into the distinct properties of wild type and mutant UBQLN2; newly generated mouse models expressing wild type or mutant UBQLN2 that show robust aggregate pathology selectively in mutant UBQLN2 mice; a completed proteomics screen demonstrating that wild-type UBQLN2 interacts with the two other brain-expressed ubiquilins, UBQLN1 and UBQLN4; and evidence that TDP43-positive cytoplasmic puncta accumulate in neurons of mutant UBQLN2 mice, offering a pathway to explore functional links between UBQLN2 and TDP43. The proposed multi-system approach greatly increases the probability of uncovering disease mechanisms in FTD/ALS and achieving our long-term objective of finding routes to therapy for this spectrum of fatal, age-related neurodegenerative diseases.
|
0.958 |
2016 — 2020 |
Paulson, Henry L |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Michigan Alzheimer's Disease Core Center @ University of Michigan At Ann Arbor
OVERALL Abstract The Michigan Alzheimer?s Disease Core Center (Michigan ADCC) aims to foster and enhance innovative research in Alzheimer?s disease (AD) and related dementias with a long term goal of developing targeted therapies for these challenging disorders. This center will build on the existing deep infrastructure and research strengths in dementia and aging research at the University of Michigan (UM). The Michigan ADCC will emphasize research that seeks to identify, understand, and modulate the non-ß-amyloid factors that contribute to brain dysfunction and neurodegeneration in AD and other dementias. The rationale for this focus is that while recent advances have defined a central role for ß-amyloid in AD, many potentially modifiable factors beyond ß-amyloid contribute to brain dysfunction and degeneration yet remain poorly understood. The Michigan ADCC will leverage established strengths in brain imaging, dementia risk identification and disclosure, mechanistic studies of neurodegenerative proteinopathies, and predictive Big Data analytics to achieve this objective. A truly regional center, the Michigan ADCC will promote research across the UM campus, throughout the state of Michigan via collaborations with our partner universities Michigan State University and Wayne State University, and across the nation through collaborations with other NIA-sponsored AD Centers (ADCs) and programs. The Michigan ADCC has four goals: 1) Foster, catalyze and perform research of the highest potential impact in AD and related neurodegenerative disorders; 2) Promote regional efforts to understand, diagnose and treat AD and related dementias through collaborative scientific and outreach efforts; 3) Provide a wide range of training and research opportunities in the dementias for health care professionals, scientists, and students through innovative educational and mentoring efforts; and 4) Collaborate with other ADCs, the NACC, and other multi-center research efforts to move the field closer to effective therapies for this group of devastating diseases. Success in achieving these goals will be ensured through the fully integrated activities of six cores (Administrative; Clinical; Data Management and Statistical; Neuropathology; Outreach and Recruitment; and Research Education Component ), and through close collaboration with related programs including the UM Protein Folding Diseases Initiative, Claude D. Pepper Older Americans Independence Center, Udall Center of Excellence for Parkinson?s Disease Research, and Healthier Black Elders Center of the Michigan Center for Urban African American Aging Research. These and other collaborations have led to newly developed emphases on the detection of early cognitive decline in an underserved population (African Americans in Detroit) and on novel potential biomarkers of disease. The Center?s extensive preliminary organization and teams of experts ensure that, upon receiving NIA designation, the Michigan ADCC will have an immediate impact, both regionally and nationally, in enhancing research to better understand and treat AD and related forms of dementia.
|
0.958 |
2016 — 2021 |
Paulson, Henry L |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Core a: Administrative Core @ University of Michigan At Ann Arbor
ABSTRACT ? CORE A: ADMINISTRATIVE CORE The key functions of the Administrative Core (AC) are to: a) maximize the local, statewide and national impact of initiatives developed and implemented by the Michigan ADRC; b) enhance collaborations across the three partner universities comprising the consortium (University of Michigan, Wayne State University and Michigan State University) and with the NACC, NCRAD and outside investigators; c) provide sound oversight for fiscal and personnel matters; and d) ensure rigor, integrity and transparency in the research and activities supported by the center. The AC?s stable leadership ensures that the various research, training and outreach initiatives managed by the Cores will maintain synergy and connection to the Michigan ADRC?s central theme, which is to identify, understand and modulate the myriad non-?-amyloid factors that contribute to brain dysfunction and neurodegeneration in AD and related dementias. The AC will ensure a broadly supportive environment for all investigators, but particularly for junior investigators, with the goal of nurturing a diverse group of next- generation leaders. To have maximal effect as an ADRC, the AC will work closely with other centers and programs across the consortium that are engaged in age-related research, including the six NIA-funded centers that together comprise the UMAging Initiative. In six aims the AC will: 1) Leverage expert dementia resources and skills focused in each Core; 2) Maintain cohesive interplay across the Cores; 3) Sustain existing and build new local and regional partnerships; 4) Sustain existing and build further national partnerships; 5) Promote efforts to address racial and ethnic disparities in ADRD; and 6) Develop next-generation leaders through diverse research and training opportunities. In its first cycle as an NIH-designated ADRC, the Michigan ADRC met its milestones due, in part, to a proactive AC that helped build key state-wide partnerships. Benefitting from close links to the many complementary NIA-funded programs on our campuses, the outstanding additional resources of all three universities, and continuing philanthropic success, the Michigan ADRC is well-positioned to further enrich innovative dementia research, outreach, and training efforts, both regionally and nationally.
|
0.958 |
2018 — 2021 |
Mcloughlin, Hayley Sarah [⬀] Paulson, Henry L |
U01Activity 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. |
Preclinical Development of Antisense Oligonucleotide Therapy For Spinocerebellar Ataxia Type 3 @ University of Michigan At Ann Arbor
Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD), is the most common dominantly inherited ataxia in the world and caused by an expansion of a polyglutamine-coding CAG repeat in the ATXN3 gene. There currently is no effective treatment for this relentlessly progressive and fatal disease. Because expression of the mutant protein is an early and necessary step in disease pathogenesis, strategies to reduce expression of the disease gene itself are high on the list of potential therapies. Our previous therapeutic studies suggested the need for broad CNS delivery of gene silencing reagents. Chemically modified ASOs can be delivered broadly to the CNS and are known to be highly stable in vivo. Prior studies employing ASOs have documented well-tolerated, long-term knockdown in mouse and non-human primate models of neurodegenerative diseases including SMA, HD and ALS. Moreover, ASO therapy in spinal muscular atrophy (SMA) was recently FDA- and EMA-approved following multiple highly successful human clinical trials. We recently established ASO therapy proof-of-concept in a SCA3 mouse model, concluding that the strategy to reduce levels of the nonessential ATXN3 disease protein in patients would likely be well tolerated. This U01 discovery proposal extends from the proof-of-concept studies to characterize a final human candidate lead ASO compound for IND-enabling studies. Aim 1 will confirm the viability of 4-6 lead ATXN3 ASOs through in vitro screens for inflammatory and off-target effects and in vivo tolerability in rodent and non-human primates that will support IND-enabling studies. Aim 2 will assess the in vivo efficacy of the lead ATXN3 ASOs to suppress mutant ATXN3 expression and ameliorate behavioral deficits, alter disease pathology and molecular signatures in a SCA3 mouse model expressing the full-length human mutant ATXN3 transcript. The results will culminate in the selection of a single lead compound for future IND-enabling studies. Concurrent with these studies, a necessary next step for therapeutic success is the optimization of SCA3 disease biomarkers that may directly assess therapeutic target engagement and treatment response. Cerebrospinal fluid (CSF) is an ideal biological sample in which to look for therapeutic biomarkers as it is readily accessible and can be sampled repeatedly throughout disease progression and therapeutic trials. Significant advances in immunoassay technology now make it possible to quantify low abundance proteins using an ultrasensitive single molecule counting (SMC) immunoassay detection system. In Aim 3, we will optimize a SMC immunoassay to detect ATXN3 protein levels from SCA3 patient CSF samples. Developing this novel ATXN3 SMC immunoassay will enable detection of in vivo therapeutic target engagement and efficacy during ASO treatment in SCA3 patients.
|
0.958 |
2021 |
Kleindorfer, Dawn O Paulson, Henry L |
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 Clinical and Basic Neuroscience @ University of Michigan At Ann Arbor
Abstract This training program in translational Neuroscience has been funded for the past 34 years, and involves the Departments of Neurology, Neurosurgery, Pediatrics, Internal Medicine, Anesthesia, Emergency Medicine, Human Genetics, Radiology, Cell & Developmental Biology, Cardiovascular Medicine, Pathology, and Epidemiology at the University of Michigan and the VA Ann Arbor Health System. Our preceptors' expertise spans the whole Neuroscience translational continuum from basic mechanistic work through preclinical research and clinical research to health services research. We train basic scientists and clinicians to conduct . research across the whole Neuroscience translational research continuum. We offer laboratory and clinical science training in neurodegenerative disorders, neuromuscular diseases, neuroinflammatory disorders, stroke, systems neuroscience, and health services research. Mentored research under the direction of established, productive investigators is the central pillar of this program. Mentored research experiences are complemented by appropriate formal education and a well-defined Core Program to advance rigorous scientific training and career progression. Laboratory based research training is largely a project oriented approach with careful mentoring by trainee preceptors. All trainees in clinical science programs are required to complete a Master's Degree, either the School of Public Health's Master's Program in Clinical Research or a unique Health Services Research Master's Program. Trainees are biomedical scientists who seek training in disease- oriented neuroscience and clinicians - neurologists, neurosurgeons, pediatricians, or other physicians - who have completed clinical training and select a laboratory-based or clinical research career. Trainees are selected competitively by the program's Executive Committee. Trainee recruitment includes a strong diversity outreach program with a ?bridging? program connecting this training program to NINDS sponsored programs aimed at increasing diversity in Neuroscience graduate student education and a particularly strong connection to the University of Puerto Rico. This training program is embedded within the rich research environment of the University of Michigan which includes a highly collegial and interdisciplinary neuroscience research community, excellent core resources for biomedical research, and strong resources for clinical and health services research. The latter include a very strong School of Public Health, a Clinical and Translational Science Award (CTSA) program, and the Institute for Healthcare Policy and Innovation, the largest academic health services research program in the USA. Individual mentors are responsible for guiding their trainees in generating research proposals, supervising trainees' work, and evaluating trainees' performance with additional mentoring provided by discipline specific committees for each trainee and general oversight by the Executive Committee. Our prior trainees have been successful in proceeding to productive careers and we annually turn away excellent applicants. For this reason, we propose to increase our trainee number to 5 postdoctoral fellows/year.
|
0.958 |
2021 |
Paulson, Henry L |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Research Education Component @ University of Michigan At Ann Arbor
ABSTRACT ? RESEARCH EDUCATION COMPONENT Effective research in Alzheimer?s disease and related disorders (ADRD) requires interdisciplinary integration of knowledge and expertise across the translational spectrum. The goal of the MADRC Research Education Component (MADRC-REC) is to foster the emergence of a new and diverse generation of investigators with domain-specific expertise, multi-disciplinary knowledge of ADRD, and orientation towards interdisciplinary work. Utilizing the resources of our three universities and the MADRC Cores, the MADRC-REC developed a model inter-institutional enhanced mentoring program for early-career investigators who were entering ADRD research. To complement our regional mentoring program, the MADRC-REC developed an on-line curriculum to broadly educate early-career investigators about key aspects of ADRD. Over the last cycle, the very diverse MADRC-REC mentees made excellent career progress. The MADRC-REC curriculum is widely used. In the next cycle, the MADRC-REC will build on existing strengths to: 1) Recruit talented early-career investigators into ADRD research; 2) Enhance early-career investigator research skills; 3) Increase the diversity of the ADRD research community; 4) Provide practical training in important career skills; 5) Implement a certificate granting Massive Online Open Course (MOOC) on the spectrum of ADRD research; and 6) Evaluate our teaching and mentoring activities. In the next cycle, the MADRC-REC will draw on the resources of the MADRC Cores, the large pool of eligible early-career investigators, exceptional number of capable mentors, and complementary career development resources of our three universities to expand our inter-institutional enhanced mentoring program. We will deepen our joint mentoring activities with other NIA sponsored programs such as the U-M Claude Pepper Older American Independence Center, the Michigan Center for Urban African American Aging Research, and the Michigan Center for Contextual Factors in Alzheimer?s Disease. The inter-institutional nature of the MADRC-REC program increases linkages and collaborations across the ADRD research community at our three universities, and enhances our mentoring of the next generation of ADRD-focused scientists and clinician-scientists.
|
0.958 |
2021 |
Paulson, Henry L |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Michigan Alzheimer's Disease Research Center @ University of Michigan At Ann Arbor
ABSTRACT ? OVERALL Four years ago the Michigan ADRC (MADRC) was established as a new consortium linking the three major research universities in Michigan: University of Michigan, Michigan State University, and Wayne State University. Serving the entire state of Michigan, the new MADRC achieved its milestones in wide-ranging activities and research that emphasized a central theme: to identify, understand and treat the myriad non-?- amyloid contributions to brain dysfunction and degeneration in Alzheimer?s disease and related dementias (ADRD). With continued NIA support, the MADRC proposes to maintain this central theme because it captures the diverse expertise of our dementia scientists, sheds light on ADRD heterogeneity, and reflects the experience of the racially diverse pool of research participants engaged in MADRC-sponsored studies. To achieve its objectives, the MADRC has four major aims: 1) Catalyze and perform research of the highest impact in ADRD; 2) Promote regional efforts to understand, diagnose and treat the full spectrum of dementias through collaborative scientific and outreach efforts; 3) Provide training and research opportunities for health care professionals, scientists, and students in ADRD through innovative educational and mentoring programs; and 4) Collaborate with other ADRCs, the NACC, NCRAD, and other multi-center efforts to lead the field in developing new diagnostic and therapeutic interventions for these devastating diseases. The integrated efforts of seven Cores, including new Neuroimaging and Biomarker cores, will support a wide range of basic, clinical, translational and health disparities research advancing the field toward: improved understanding of disease mechanisms; more precise disease identification across the dementia spectrum; development of novel biomarkers; increased knowledge of the basis for health disparities that disproportionately affect Black Americans; development of non-pharmacological therapies; and the identification and modification of disease risks. The Research Education Component (REC) will serve as the centerpiece of innovative training opportunities spanning all the Cores, and a new Leaders Initiative will support and promote a diverse group of next-generation leaders in dementia research. Benefitting from the outstanding resources of all three universities and strong multi-institutional support, the MADRC is poised to make new discoveries, educate the public, and train next-generation leaders as we seek to achieve the milestones set forth in the National Alzheimer?s Project Act.
|
0.958 |
2021 |
Paulson, Henry L |
R35Activity Code Description: To provide long term support to an experienced investigator with an outstanding record of research productivity. This support is intended to encourage investigators to embark on long-term projects of unusual potential. |
Mechanisms of Neurodegenerative Diseases: Intersections With Ubiquitin Pathways @ University of Michigan At Ann Arbor
This R35 proposal builds on the principal investigator?s longstanding success seeking the causes of age- related neurodegenerative diseases and developing treatments for these devastating and largely fatal disorders. The proposal?s unifying theme is a focus on proteins that participate in ubiquitin-linked quality control pathways and that are prone, in neurodegenerative diseases, to phase-separate and aggregate. Building on our recent discoveries in polyglutamine-mediated neurodegeneration and brain-expressed ubiquilins (a class of proteins implicated in various neurodegenerative diseases), we will apply multi-scalar approaches to define pathogenic mechanisms, emphasizing intersections with ubiquitin-dependent pathways in the search for novel therapeutic targets. The importance of ubiquitin in the nervous system extends far beyond its classically defined degradative role in the ubiquitin-proteasome system. But how the broader ubiquitin signaling system is impaired by, or activated in response to, diseases of the nervous system represents a significant gap in current knowledge. Leveraging a broad suite of innovative tools/models and an exceptional research environment, we will address fundamental issues of broad relevance to age-related neurodegeneration. These topical issues include: the impact of altered ubiquitin signaling in the nucleus; the contribution of altered ubiquitin homeostasis to selective cell type and regional vulnerability; and the relationship between mutation-induced changes in phase transitions undertaken by disease proteins, altered function in ubiquitin-linked pathways, and toxicity in the nervous system. The discoveries we make through the R35 will help define the complex biological roles of ubiquitin in diseases of the nervous system, highlight potential shared elements of disease pathogenesis, and identify promising therapeutic targets that could drive the development of treatments for neurodegenerative disorders.
|
0.958 |