1988 — 1992 |
Albin, Roger L |
K08Activity Code Description: To provide the opportunity for promising medical scientists with demonstrated aptitude to develop into independent investigators, or for faculty members to pursue research aspects of categorical areas applicable to the awarding unit, and aid in filling the academic faculty gap in these shortage areas within health profession's institutions of the country. |
Huntington Disease and Quinolinate--Striatal Cell Types @ University of Michigan At Ann Arbor
We propose to study the relative loss or preservation of subpopulations of striatal neurons in Huntington's disease (HD) and the quinolinic acid (QA) model of HD. Recent research has shown that some striatal neurons are preferentially affected and others relatively spared in HD. These findings give clues to the pathogenesis of cell death in HD. An understanding of pathogenesis will be necessary for the development of a therapy for HD and may aid in the understanding of other degenerative disorders of the nervous system. Knowledge of changes in striatal neuron subpopulations also provide a tool with which to evaluate and develops models of HD pathogenesis. An accurate model would greatly facilitate the understanding of HD pathogenesis and pathophysiology. Our specific aims are: 1) To continue present research on changes in striatal efferent peptidergic neurons in HD. Using immunocytochemistry, we have been able to correlate these changes with some of the clinical and pharmacological features of HD. 2) To apply a set of criteria derived from studies of striatal neuron sub-populations in HD to the established QA model of HD. Utilizing an acute QA striatal lesion paradigm in rats, we will examine the effects of QA on both striatal interneurons and identify NADPH-diaphorase containing and cholinergic interneurons. The latter will be examined using immunocytochemistry to identify striatal efferent peptidergic neurons and quantitative autoradiography to assess receptor changes in striatal target areas. 3) To develop a model of HD that more closely approximates the characteristics of the disease. The striatum of the rat is substantially different from that of primates. We will evaluate acute QA striatal lesions in cats, whose striatum appears to be quite similar to that of primates. Finally, we will develop a new paradigm of chronic subthreshold intoxication and evaluate it in both rats and cats.
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1 |
1996 — 1998 |
Albin, Roger L |
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. |
Chronic Striatal Quinolinate @ University of Michigan At Ann Arbor
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by dementia, personality changes, and movement disorders. Knowledge of the pathogenesis of neuronal death in HD may lead to insights into the pathogenesis of other dementing illnesses. The striatum is prominently affected in Huntington's disease. Some evidence indicates that striatal damage caused by acute intrastriatal administration of N-methyl-D-aspartate (NMDA) agonists is a good experimental model of HD, implying that excessive NMDA receptor activation is involved in neuronal death in HD. The present model has several drawbacks; 1) controversy over some aspects of the model; 2) limited usefulness as a technique for preclinical evaluation of potential therapies; 3) lack of knowledge about how NMDA receptors might become excessively activated in HD. We have developed a new model of HD utilizing chronic intrastriatal administration of the NMDA agonist quinolinic acid (QA). Our preliminary data indicates that chronic intrastriatal Qa administration is a good experimental model of HD. We propose to further evaluate the consequences of intrastriatal QA administration to demonstrate that chronic QA administration does replicate the histopathology of HD. Our model provides a better means of evaluating potential therapies for HD and we will use this model to test the efficacy of systemically administered NMDA antagonists, co-administered nitric oxide synthase inhibitors, and fetal striatal grafts. Finally, chronic administration will be used to explore a mechanism that might lead to excessive NMDA receptor activation by studying the potential neurotoxic consequences of disrupting striatal energy metabolism.
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1 |
1996 — 1999 |
Albin, Roger L |
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. |
Pet Studies of Hyperkinetic Movement Disorders @ University of Michigan At Ann Arbor
The pathophysiology of hyperkinetic movement disorders is incompletely understood. This lack of knowledge is an obstacle to the development of better symptomatic therapies. We will explore the pathophysiology of hyperkinetic movement disorders using emission tomography with ligands aimed at striatal muscarinic cholinergic receptors striatal dopaminergic terminals and striatal cholinergic terminals. We hypothesize that dystonias are characterized by excessive striatal cholinergic neurotransmission and downregulation of striatal cholinergic receptors. We predict decreased muscarinic cholinergic receptor binding with normal striatal cholinergic innervation and will test this hypothesis using [11C]N-methylpiperidyl benzilate (NMPB) to measure striatal muscarinic cholinergic receptors and (-)-5-[123I]iodobenzovesamicol to measure striatal cholinergic terminals, respectively. In Tourette's syndrome, we hypothesize that there is excessive striatal dopaminergic innervation and excessive striatal cholinergic neurotransmission. We predict increased density of striatal dopaminergic terminals and decreased striatal cholinergic receptor binding. We will test these predictions with [11C]dihydrotetrabenazine (DTBZ) and [11C]NMPB. We hypothesize that the degree of dopaminergic innervation is an important determinant of the type of movement disorder suffered by Huntington's disease patients with marked rigidity resulting from degeneration of dopaminergic neurons. We will test this hypothesis by correlating character of the movement disorder with the results of [11C]DTBZ scans. We predict significantly diminished [11C]DTBZ binding in rigid but not in choreic Huntington's disease patients.
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1 |
1999 — 2002 |
Albin, Roger 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. |
Murine Model of Cag Repeat Diseases @ University of Michigan At Ann Arbor
Several human neurodegenerative disorders are caused by CAG/polyglutamine repeat expansions within different genes. The preponderance of evidence suggests 'gain of function' effects at the protein level in which excessive polyglutamine tracts gain new and toxic properties. Some evidence suggests that proximate mechanisms of neurodegeneration are excitotoxic, perhaps rooted in mitochondrial dysfunction. We have developed a novel model of CAG repeat disorders by inserting a 146 unit CAG repeat disorders by inserting a 146 unit CAG repeat into the murine hypoxanthine phosphoribosyltransferase (Hprt) locus. These animals exhibit adult onset behavioral abnormalities, premature death, and neuronal intranuclear inclusions recognized recently to be characteristic of human CAG repeat diseases. Preliminary histologic analysis has not disclosed obvious neurodegeneration. A model of CAG repeat disorders that could be used to explore the pathogenesis of neurodegeneration and for preclinical intervention studies would exhibit behavior abnormalities, premature death, and neurodegeneration. We will carry out unbiased stereological analysis of neuronal density in selected brain regions in hprt/(CAG)146 mice to uncover subtle evidence of neurodegeneration. We will attempt extension of life span in HPRT-CAG mice in the hope of observing gross neurodegeneration. Neuronal intranuclear inclusions are suspected of being instrumental in causing neurodegeneration. We will correlate the development of neuronal intranuclear occlusions with the development of behavioral abnormalities and, if possible, with the development of neurodegeneration. Expanded CAG repeats may cause mitochondrial dysfunction and increased sensitivity to excitotoxic agents and mitochondrial toxins. We will use biochemical and histochemical methods to evaluate mitochondrial function in hprt(CAG)146 mice. We will determine the sensitivity of hprt/(CAG)146 mouse brains to mitochondrial toxins and excitotoxins. These experiments will establish HPRT-CAG mice as important tools for understanding neurodegeneration in CAG repeat diseases and enable accurate preclinical evaluation of interventions for CAG repeat diseases.
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2002 — 2007 |
Albin, Roger L |
U10Activity Code Description: To support clinical evaluation of various methods of therapy and/or prevention in specific disease areas. These represent cooperative programs between sponsoring institutions and participating principal investigators, and are usually conducted under established protocols. |
Michigan Parkinson's Disease Clinical Center @ University of Michigan At Ann Arbor
[unreadable] DESCRIPTION (provided by applicant): This is an application for a Parkinson's Disease Clinical Center (PDCC) at the University of Michigan. The goals of this PDCC are identification of subjects with early, mild Parkinson's disease (PD), their recruitment into pilot and large, multi-arm trials of neuroprotective treatments, follow up of recruited subjects until trial completion, and post-trial follow up of subjects to ascertain the presence of treatment effects. Subjects will be recruited from the existing referral base of clinics at the University of Michigan, the Ann Arbor Veterans Affairs Medical Center, via state-wide publicity of the trial to neurologists in Michigan, and through the major lay PD organization in Michigan, the Michigan Parkinson's Foundation (MPF). We are already working with the MPF on statewide educational and clinical care activities for PD. The established collaborations and state-wide range of activities will enhance recruitment of appropriate subjects within Michigan. Subjects will be enrolled and followed by experienced Movement Disorder clinicians with prior significant experience in clinical trials. Our center has developed a promising objective marker of disease progression; [14C]dihydrotetrabenazine positron emission tomography (DTBZ-PET). A subset of subjects recruited at our site and surrounding sites could be followed serially with DTBZ-PET. In pilot trials, this subset could be used to evaluate DTBZ-PET as a biomarker of disease status and possibly as a screening method for evaluation of putative neuroprotective agents. In large, multi-arm trials, a subset of patients would be followed with DTBZ-PET as an objective marker of disease progression. The use of DTBZ-PET will be enhanced by sharing of subjects from other PDCCs within Michigan to ensure efficient use of PET imaging.
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2004 |
Albin, Roger L |
M01Activity Code Description: An award made to an institution solely for the support of a General Clinical Research Center where scientists conduct studies on a wide range of human diseases using the full spectrum of the biomedical sciences. Costs underwritten by these grants include those for renovation, for operational expenses such as staff salaries, equipment, and supplies, and for hospitalization. A General Clinical Research Center is a discrete unit of research beds separated from the general care wards. |
Minocycline &Creatine in Subjects W/ Early Untreated Parkinson's Disease @ University of Michigan At Ann Arbor
human therapy evaluation; Parkinson's disease; brain disorder chemotherapy; tetracyclines; antibacterial agents; drug interactions; creatine; patient oriented research; human subject; clinical research;
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1 |
2005 — 2006 |
Albin, Roger L |
M01Activity Code Description: An award made to an institution solely for the support of a General Clinical Research Center where scientists conduct studies on a wide range of human diseases using the full spectrum of the biomedical sciences. Costs underwritten by these grants include those for renovation, for operational expenses such as staff salaries, equipment, and supplies, and for hospitalization. A General Clinical Research Center is a discrete unit of research beds separated from the general care wards. |
Coq10 and Gpi 1485 in Subjects With Early Untreated Parkinson's @ University of Michigan At Ann Arbor |
1 |
2005 — 2009 |
Albin, Roger L |
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. |
Differentiating Degenerative Dementia With [11c]Dtbz-Pet Imaging
There are 3 major forms of degenerative dementia;Alzheimer disease (AD), Dementia with Lewy bodies (DLB), and Frontotemporal Dementias (FTD). Convergent clinical, pathologic, and genetic data indicate that these degenerative dementias have different mechanisms of pathogenesis. It is likely that different treatments will be needed to alter the course of these disorders. Appropriate application of treatments will require precise and early diagnosis. Precise, early diagnosis would be very useful now to improve clinical trial performance. Improved precision of initial diagnosis would also be valuable for present clinical practice. Certain differentiation of these entities is possible with postmortem evaluations only. Clinical criteria exist to guide ante-mortem diagnosis but these criteria are imprecise. Differentiating DLB and FTD from AD is particularly difficult, especially in individuals with mild-early dementia. Imaging methods may improve the precision of initial diagnosis. We found that quantifying nigrostriatal dopamine terminals robustly differentiates AD and DLB. FTD may be differentiated from AD and DLB by distinctive patterns of regional cortical hypometabolism. We have developed a method, [11C]dihydrotetrabenazine positron emission tomography (DTBZ-PET), that quantifies nigrostriatal terminal density and assesses regional cortical perfusion as a faithful analogue of regional cortical metabolism. Our preliminary data suggests that this method will permit early, accurate differentiation of AD, DLB, and FTD. Our goal is to develop an imaging method to permit early and accurate differentiatal diagnosis of early mild dementia. We propose a prospective evaluation of the ability of DTBZ-PET to differentiate the 3 major degenerative dementias in subjects with early-mild dementia. Our hypothesis is that the results of DTBZ-PET imaging in subjects with mild, early dementia will predict their evolution into clinically distinguished AD, FTD, and DLB. Our first specific aim is to determine nigrostriatal terminal density and patterns of regional cortical perfusion in a cohort of well characterized subjects with early-mild dementia. Our second specific aim is respectively to follow and characterize this cohort with standardized clinical and psychometric evaluations. Our third specific aim is to correlate the clinically and psychometrically established diagnoses with diagnoses predicted by DTBZ-PET. If successful, these studies would strongly support the use of DTBZ-PET imaging or similar methods in the evaluation of early dementia.
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1 |
2005 — 2007 |
Albin, Roger L |
M01Activity Code Description: An award made to an institution solely for the support of a General Clinical Research Center where scientists conduct studies on a wide range of human diseases using the full spectrum of the biomedical sciences. Costs underwritten by these grants include those for renovation, for operational expenses such as staff salaries, equipment, and supplies, and for hospitalization. A General Clinical Research Center is a discrete unit of research beds separated from the general care wards. |
Dopamine Synaptic Mechanisms in Tourette Syndrome @ University of Michigan At Ann Arbor |
1 |
2005 |
Albin, Roger L |
M01Activity Code Description: An award made to an institution solely for the support of a General Clinical Research Center where scientists conduct studies on a wide range of human diseases using the full spectrum of the biomedical sciences. Costs underwritten by these grants include those for renovation, for operational expenses such as staff salaries, equipment, and supplies, and for hospitalization. A General Clinical Research Center is a discrete unit of research beds separated from the general care wards. |
Minocycline &Creatine in Subjects W/ Early Untreated Parkinson?S Disease @ University of Michigan At Ann Arbor |
1 |
2006 — 2007 |
Albin, Roger 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. |
Evaluating Striatal Function in a Murine Hd Model @ University of Michigan At Ann Arbor
[unreadable] DESCRIPTION (provided by applicant): Evaluating Striatal Function in a Murine HD Model Murine genetic models have been developed for Huntington's disease (HD). Appropriate behavioral evaluations are crucial for preclinical evaluation of treatments proposed for humans. Behavioral evaluation in these murine models has been limited largely to assessment of motor function or use of learned behaviors that largely preclude serial evaluations in the same animals. Available data indicates that the most genetically accurate models, so-called 'knockin' models, exhibit pathology relatively restricted to the striatum. Presently used behavioral measures do not assess striatal function specifically. We hypothesize that behavioral measures assessing known striatal functions will be more sensitive measures of behavioral abnormalities in an HD knockin model than previously used behavioral measures. We have chosen two behaviors regulated normally by the striatum, control of grooming sequences and egocentric spatial memory that can be assessed serially in the same animals by simple behavioral methods. We compare assessment of grooming sequences and egocentric spatial memory function with conventional behavioral methods in HD knockin and control littermate mice. We predict that our chosen novel methods will prove more efficient at identifying phenotypic abnormalities than conventional behavioral methods. Validation of these methods will provide new and useful behavioral tools for evaluating murine disease models. [unreadable] [unreadable] [unreadable]
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2008 — 2012 |
Albin, Roger 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. |
Serotonin and Sleep Disordered Breathing in Parkinson Disease
PROJECT 3 SEROTONIN AND SLEEP DISORDERED BREATHING IN PARKINSON DISEASE Sleep disturbance and excessive daytime somnolence are important non-motor/non-dopaminergic features of Parkinson disease (PD). Sleep disruption in PD is likely multifactorial but recent evidence suggests a high prevalence of sleep disordered breathing in PD, a surprising finding in view of the tendency for PD subjects to lose weight during their illness. PD is clearly a multisystem neurodegeneration with evidence indicating degeneration of central serotoninergic systems. Caudal brainstem serotoninergic neurons are key actors in controlling upper airway patency during sleep and degeneration of this group of neurons would be a plausible cause of sleep disordered breathing in PD. Our hypothesis is that loss of caudal brainstem serotoninergic neurons causes SDB in PD. We will evaluate this hypothesis by comparing the caudal brainstem [11C]DASB binding, a measure of serotoninergic neurons, in PD subjects with and without SDB. We predict greater loss of caudal brainstem [11C]DASB binding in PD subjects with SBD than in PD subjects without SDB. We predict an inverse correlation between indices of SDB and caudal brainstem [11C]DASB binding in PD subjects.
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2008 — 2009 |
Albin, Roger L |
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.) |
Neurodegeneration in Aging Retarded Mice @ University of Michigan At Ann Arbor
[unreadable] DESCRIPTION (provided by applicant): Neurodegenerative disorders, both sporadic and inherited, are associated commonly with aging. The wide variety of likely mechanisms of action in different neurodegenerative disorders suggests that common features of normal aging underlie the increased predisposition to suffer from neurodegenerative disorders. The age dependence of neurodegeneration is unexplained and is a fundamental problem in understanding these common pathologies. Understanding the interaction of aging with neurodegeneration requires the development of model systems in which the rates of aging and neurodegeneration can be varied systematically. The development of murine genetic models of polyglutamine (polyQ) diseases with varying phenotypes and the existence of mouse lines with retarded aging offers the opportunity to develop models in which the interaction of aging and neurodegeneration can be studied systematically. We propose to develop compound mice lines carrying alleles that cause polyQ disease phenotypes and alleles that retard normal aging to study the impact of altering aging on the polyQ disease-like phenotypes. We focus on a phylogenetically conserved signaling pathway that influences aging in several invertebrate and vertebrate species; the Growth Hormone-insulin/IGF - Aki - FOXO pathway. Our hypothesis is that retarding aging by disrupting the Growth Hormone - insulin/IGF - Akt - FOXO pathway will delay mortality, and retard the development of behavioral and pathologic abnormalities secondary to induced polyQ mutations. This hypothesis is supported by impressive work in invertebrates but has not been tested in mammals. Our specific aims are: 1) To generate compound mutant mice carrying a dominant HD-like transgene responsible for a moderately aggressive phenotype and 2 copies of a null mutation at the Pit1 (Snell dwarf) locus. 2) To generate compound mutant mice carrying a dominant HD-like transgene responsible for a moderately aggressive phenotype and 2 copies of a null mutation mutation at the Growth Hormone receptor (GHR) locus. 3) To characterize the lifespan, and behavioral and pathologic features of these compound mutants. Our long term goal is to understand the interaction of aging and neurodegeneration. If these experiments are successful, we will have models in hand to study the aging-neurodegeneration relationship. These models would be useful in dissecting the specific mechanisms underlying the aging-neurodegeneration relationship. We would be able to vary the rate of neurodegeneration by developing additional compound models with more slowly progressive polyQ disease alleles. We would be able to extend these approaches also to other neurodegenerations such as Alzheimer disease and Motor Neuron disease. PUBLIC HEALTH RELEVANCE The onset of most degenerative brain diseases, like Alzheimer disease and Parkinson disease, occurs later in life. Some unknown features of aging make the human brain susceptible to these degenerative disorders. We propose to develop new mouse models that will allow analysis of the interaction of normal aging and neurodegeneration. [unreadable] [unreadable] [unreadable]
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2014 — 2015 |
Albin, Roger L |
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.) |
Cholinergic Interneurons in Tourette Syndrome
DESCRIPTION (provided by applicant): Tourette syndrome (TS) is a common childhood-onset neurodevelopmental disorder characterized by multiple motor and phonic tics. TS is accompanied commonly by behavioral co-morbidities, including obsessive compulsive disorder (OCD) and attentional deficits. The pathogenesis and pathophysiology of TS are understood only poorly. Converging evidence points to striatal dysfunction in TS and a modest amount of post-mortem data suggests deficits in some populations of striatal interneurons, notably cholinergic interneurons. Striatal cholinergic interneurons are important actors within the basal ganglia. This relatively sparse population of interneurons may serve a synchronizing role across large volumes of the striatum. Deficient striatal cholinergic interneurons are a plausible substrate for tics and related manifestations of TS and we hypothesize diminished striatal cholinergic interneurons in TS. It has not been previously feasible to quantify striatal cholinergi interneuron integrity in vivo. Our group developed a novel positron emission tomography (PET) tracer, [18F]FEOBV, a ligand for the vesicular acetylcholine transporter (VChT), that allows accurate quantification of striatal cholinergic terminals in humans. We propose to evaluate striatal cholinergic neuron terminal integrity in TS and control subjects. We will recruit TS and age-matched control subjects for study with [18F]FEOBV. Subjects will undergo a standard clinical evaluation including assessment of tic severity and character, obsessive-compulsive behaviors, and attentional deficits. Primary analysis will be comparison of striatal [18F]FEOBV binding between TS and control subjects. Secondary analyses will include correlation of striatal [18F]FEOBV binding with clinical ratings and assessment of cholinergic terminal integrity in other brain regions. Validation of this hypothesis would point to a specific anatomic - neurochemical system deficit in TS. This would facilitate research on understanding the developmental basis for TS. Cholinergic systems offer multiple potential targets for pharmacologic intervention and validation of this hypothesis would initiate a new approach to experimental therapeutics in TS.
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2014 — 2021 |
Albin, Roger 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. |
Um Clinical Neuroscientist Training Program
DESCRIPTION (provided by applicant): There is a marked gap between our ability to treat neurologic diseases and our rapidly increasing understanding of normal nervous system function, disease pathogenesis, and disease pathophysiology. Improving treatment of neurologic diseases requires considerably improved integration of burgeoning basic neuroscience with clinical practice across the translational spectrum from basic discovery through preclinical and clinical research to implementation. An obstacle to improved integration of disease-oriented neuroscience research activities and more efficient translation is a deficit of appropriately trained clinician-neuroscientists. American medical schools graduate significant numbers of physicians with substantial research experience, including MD/PhDs and individuals with significant experience with and formal training in clinical and policy research. The traditionl clinical training structure, however, impedes the ability of these talented and well trained individuals to efficiently initiate productive, independent research careers. We propose a residency- fellowship based training program integrating residency-fellowship based clinical training with mentored research training to move talented and experienced trainees in Neurology, Neurosurgery, and Neuropathology to the initial stage of an independent career. The goal of the University of Michigan Clinical Neuroscientist Training Program (UMCNTP) is prepare talented clinician-neuroscientists for independent research careers across the full spectrum of disease-oriented neuroscience research. The UMCNTP is an integrated residency- fellowship program to prepare talented fledgling clinician-neuroscientists for successful applications for initial independent career support. The UMCNTP melds productive mentored research experience under the guidance of experienced senior investigators with focused didactic and hands-on career training to prepare UMCNTP trainees for successful career development applications such as K08, K23, VA CDA, or equivalents. The UMCNTP features a strong roster of mentors in the Depts. of Neurology, Neurosurgery, and Pathology, a training program based on highly successful prior experiences with training clinician-neuroscientists, utilizes excellent career development resources available at the University of Michigan, and draws on the great diversity and general excellence of the Neuroscience research community of the University of Michigan.
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2014 |
Albin, Roger L |
R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
Serotonin and Amyloidopathy
DESCRIPTION (provided by applicant): Amyloidopathy is an important feature of several dementias - Alzheimer disease (AD), Dementia with Lewy Bodies (DLB), and Parkinson disease dementia (PDD). Amyloid (Ab) peptide production is an important therapeutic target. Experimental in vitro and murine genetic model experiments indicate that Ab peptide production is reduced by activation of some G-protein coupled receptors, including serotonin receptors. Modest human data supports these interesting observations. Based on preliminary studies, our central hypothesis is that serotoninergic neurotransmission inhibits Ab amyloid production-deposition. An important corollary of this hypothesis is that diminished regional serotoninergic innervation should correlate inversely with Ab deposition. Parkinson disease (PD) - a disorder characterized by variable degeneration of serotoninergic projection systems and variable Ab peptide deposition - provides a model to evaluate this corollary prediction. In preliminary PET imaging studies of PD subjects, we found a strong inverse correlation between regional forebrain serotoninergic innervation and Ab deposition as measured with the serotonin transporter ligand [11C]DASB and the amyloid ligand [11C]PiB, respectively. These intriguing data are limited by relatively small sample size and cross-sectional study design. We propose a larger longitudinal study of PD subjects that will yield more specific assessments of the interactions between serotoninergic system changes and brain Ab amyloid deposition. To determine if the relationship between regional serotoninergic innervation and Ab amyloid deposition is generalizable, we will perform a parallel cross-sectional study in a sample of cognitively asymptomatic elderly controls. Validation of our predictions will strongly support the implementation of clinical investigations in PD and other pre-dementias aimed at using serotoninergic agents to modify the natural history of cerebral Ab peptide production-deposition. Falsification of our predictions will be equally valuable as it would undermine the central hypothesis and forestall the implementation of clinical trials of serotoninergic agents as disease modifying agents in MCI, AD, DLB, and PD.
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1 |
2014 — 2018 |
Albin, Roger L |
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. |
Alpha4beta2 Nachrs, Gait, and Balance in Pd @ University of Michigan At Ann Arbor
Project III: Summary/Abstract Abnormalities of balance and gait are common in Parkinson disease (PD), are largely unresponsive to dopamine replacement therapies, have no medical treatment options, and are major sources of morbidity. Our prior work, which will be further developed in Project II, indicates that degeneration of corticopetal basal forebrain (BF) and diffusely projecting brainstem peduculopontine (PPN) cholinergic neurons, in the context of deficient striatal dopaminergic function, contribute significantly to the progressive balance and gait deficits of PD (?3 Hit model?; detailed in Overview). This 3 Hit model proposes that a key mechanism of falls in PD is loss of cholinergic-mediated attentional compensation necessary to maintain gait in the hypodopaminergic state. ?4?2* nicotinic cholinergic receptors (nAChRs) are important mediators of CNS cholinergic neurotransmission subserving attention. Based on published human and animal data, and new preclinical data (Project I), our central hypothesis is that insufficient activation of ?4?2* nAChRs secondary to degeneration of cholinergic projections is a critical contributor to balance and gait deficits in PD. ?4?2* nAChRs are highly regulated ligand-gated ion channels and potential targets for pharmacotherapy to ameliorate balance and gait problems in PD. In this pilot target engagement study, we will study the subgroup of PD subjects with significant loss of cholinergic neurons, which will be identified by Project II and the Clinical Resource Core. We will evaluate key pharmacokinetic-pharmacodynamic features of ?4?2* nAChRs in the hypocholinergic, degenerating PD brains of these subjects using the ?4?2* nAChR partial agonist varenicline (VCN), PET imaging of ?4?2* nAChRs, and laboratory measures of gait function, postural control, and attentional function. We will use [18F]flubatine PET to determine the minimum VCN dose producing high ?4?2* nAChR occupancy in the hypocholinergic PD brain. Subacute VCN administration will be used to assess the effects of ?4?2* nAChR stimulation on gait function, postural control, and attentional function in hypocholinergic PD subjects. We predict that improved attentional function will correlate with improved gait function and postural control. These results will identify ?4?2* nAChRs as targets for future clinical trials in a well defined subgroup of PD patients, validate the novel animal model used in Project I, improve understanding of the mechanisms underlying gait and balance problems in PD, and implement new methods for evaluation of agents aimed at improving gait function and postural control deficits in PD. This work is directly responsive NINDS PD 2014 Research Report ?highest priority recommendations? calling for studies aimed at understanding mechanisms of and developing treatments for balance and gait disorders in PD (Clinical recommendations 2 & 3; Basic recommendation 3; Translational recommendation 6) and the Udall RFA request for pilot target engagement/pharmacodynamics studies.
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1 |
2016 — 2020 |
Albin, Roger 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 F: Research Education Component (Rl5) @ University of Michigan At Ann Arbor
CORE F: RESEARCH EDUCATION COMPONENT (RL5) Abstract Alzheimer?s disease (AD) and other dementias are complex, multidimensional entities. Developing effective therapies and prevention strategies will require integration of knowledge and expertise across the translational spectrum, from basic science research to implementation research. Accomplishing this goal requires a new generation of investigators possessing domain-specific expertise, broad knowledge of other disciplines relevant to the dementias, and strong orientation towards interdisciplinary work. The Research Education Component (REC) is poised to employ the Michigan ADCC?s Core leaders and teams of experts in an integrated mentoring approach with selected fellows and junior faculty. In collaboration with the other ADCC Cores and building on existing R25 and T32 mechanisms, the REC will implement inter-disciplinary mentoring programs for selected fellows and junior faculty. The overarching goal of the REC is to identify and mentor talented junior investigators in interdisciplinary dementia-related research across the translational spectrum. The objectives of the REC are to recruit talented junior investigators into dementia research, to enhance junior investigator research skills, to equip fellows and junior faculty at the earliest stages of their careers with a broad knowledge of dementias, to assist junior investigators with development of crucial practical skills in crafting successful grant support applications, and to provide general career mentorship by experienced investigators. Five specific aims are proposed to achieve these objectives. Aim 1: Recruit talented junior investigators into interdisciplinary dementia research; Aim 2: Enhance junior investigator research skills; Aim 3: Develop a comprehensive, interdisciplinary curriculum to educate junior investigators about the broad spectrum of dementia research; Aim 4: Provide practical training in crucial career skills including grant preparation and oral presentation skills; and Aim 5: Enhance the diversity of investigators working on dementia-related research. The REC will achieve its aims by drawing on the diverse expertise available in the Michigan ADCC Cores, and the extraordinary number of talented senior investigators and abundant career development resources available at the three universities comprising the ADCC. In particular, REC collaborations with the Michigan Center for Urban African American Aging Research, the Study of Latinos- Investigation of Neurocognitive Aging (SOL-INCA) project, and the Claude D. Pepper Older American Independent Center will be instrumental in achieving these five goals. Many candidate junior investigators have already been identified, of whom five are presented as strong REC candidates for year one, with mentoring plans for their career development offered as examples of future REC activities.
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1 |
2018 — 2021 |
Albin, Roger L Chou, Kelvin L |
U24Activity Code Description: To support research projects contributing to improvement of the capability of resources to serve biomedical research. |
Neuronext Clinical Research Site At the University of Michigan @ University of Michigan At Ann Arbor
The Network of Excellence in Neuroscience Clinical Trials (NeuroNEXT), sponsored by NINDS, is designed to create infrastructure accelerating clinical trials for neurologic diseases in children and adults. This project will establish a Clinical Trials Site at the University of Michigan (UM) as part of the NeuroNext consortium. UM has a strong tradition in clinical neurosciences research, including clinical trials, and outstanding institutional resources to facilitate clinical trials. These include a centralized Clinical Trials Support Office, a robust pool of clinical research coordinators, strong institutional commitment to clinical trials, access to broad and diverse patient populations, and a diverse group of accomplished clinical investigators. These attributes qualify the University of Michigan as a productive NeuroNEXT site. Our goals as a NeuroNEXT site are to participate in a minimum of 4 NeuroNEXT trials over the course of the 5 year award, to provide substantial support for other NINDS sponsored trials, to coordinate our institutional resources at UM with the shared NeuroNEXT network infrastructure to increase efficiency, and to provide support and resources for clinical research training in order to develop the next generation of neurologic disease clinical trialists. To accomplish these goals, we will abide by a master clinical trial agreement and use a centralized IRB. The UM NeuroNEXT site will be led by two experienced Principal Investigators with track records in NINDS-, foundation- and pharmaceutical-supported clinical trials and will be administered by an Operating Committee. The Operating Committee will be responsible for the major decisions required in operating the UM NeuroNEXT program, including reviewing the approved clinical protocols received from NINDS, selecting the appropriate lead investigator among the UM NeuroNEXT site faculty to assume responsibility for the trial, providing the clinical and administrative support to conduct the trial rapidly and efficiently, as well as tracking and reporting trial performance to NINDS on a regular basis. A Training Program consisting of a mentorship program, a didactic learning experience, and clinical trial participation will also be part of the UM NeuroNEXT site to assist early stage clinical investigators in developing the skills needed to pursue careers in academic clinical research.
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2019 |
Albin, Roger L |
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. |
Project Iii, Cholinergic Pathology as An Early Marker of a Parkinson Disease Subgroup @ University of Michigan At Ann Arbor
Project III: Summary/Abstract Parkinson disease (PD) is a highly heterogeneous syndrome with marked differences in progression of motor and cognitive features. PD heterogeneity suggests the existence of subgroups, but there is little success to date in subgroup identification. Subgroup identification would advance the critically important goal of enabling focused or appropriately stratified trials and enhance clinical care by providing better prognostic information. In the prior cycle of this Udall Center, we identified specific regional cholinergic deficits underlying distinct gait- balance deficits, reflecting distorted attentional-motor integration (Overall Component, Projects I & II). We used [18F]FEOBV PET to establish a deeply phenotyped non-demented PD cohort including a substantial subgroup with loss of occipital cortical cholinergic afferents. Our findings (Overall Component, Projects II & III) and those of others demonstrate that cholinergic deficits are an important determinant of heterogeneous clinical features and heterogeneous rates of motor progression and cognitive decline, likely caused by distorted integration of attention and other cognitive functions. Based on our results and other data, our central hypothesis is that early loss of occipital cortical cholinergic afferents identifies a PD subgroup with accelerated motor and cognitive decline. We will test this hypothesis with a prospective, longitudinal study of our uniquely phenotyped PD subject cohort. Importantly, we will further test our findings in an independent replication cohort of incident PD subjects that are similarly phenotyped, including with [18F]FEOBV imaging. This unique feature, made possible because of a valuable international collaboration, will ensure that our findings are derived using rigorous methodology. Future assessments of a hypocholinergic PD subgroup would be greatly facilitated by the identification of clinical features reflecting [18F]FEOBV abnormalities. We will also use our extensive phenotypic dataset and modern data-driven methods to identify easily accessible clinical markers of diminished occipital cortical cholinergic afferents in our Udall cohort, and validate these findings in the incident PD cohort. Together with the University of Rochester Udall and a U-M expert in human subject tracking technology, we will also assess in-home sensor evaluations of gait and balance functions as a clinical marker of occipital cortical cholinergic afferent loss. This work is directly responsive to the NINDS PD 2014 Research Report highest priority recommendations calling for development of ?patient stratification tools that define disease signatures of more homogeneous cohorts with emphasis on slow- vs. fast-progressing PD, ? and non-motor symptoms? (Translational Research Recommendation #1), and development of ?companion biomarkers for dopa-resistant features of PD?especially cognitive impairment?? (Clinical Research Recommendation #2). This clinical project addresses one of the needs described in most recent Udall Centers RFA, ?Identification of patient subgroups?to inform clinical trial design.? Drawing directly on our prior studies of disrupted attentional- motor integration in PD secondary to cholinergic system deficits, we will develop useful tools for clinical research and clinical practice.
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2019 — 2021 |
Albin, Roger L |
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. |
Cholinergic Mechanisms of Attentional-Motor Integration and Gait Dysfunction in Parkinson Disease @ University of Michigan At Ann Arbor
Progressive gait and balance difficulties, and associated falls, are among the most common levodopa resistant symptoms in Parkinson disease (PD), eventually occurring in nearly all patients. During the current funding period, U-M Udall Center research demonstrated a far more prominent, dynamic and multifaceted role for cholinergic signaling in PD gait abnormalities than previously appreciated. These insights position us to establish a systems neuroscience model of circuit interactions in gait by pursuing an interrelated and complementary set of clinical and basic studies, and to perform the first prospective assessment of cholinergic deficits as a biomarker of clinical heterogeneity in PD. Considerable data, including that developed during the current funding period, demonstrates that normal gait and posture depend on integration of sensory-attentional and motor information, and that cholinergic neurotransmission is vital for normal ?attentional-motor? interface at multiple CNS sites. These data support a novel, mechanistic model of attentional-motor interactions that will be tested with the studies proposed. Project I will dissect, in a rodent model, the role of cholinergic neurotransmission in detecting, transferring, and integrating attentional information as it traverses corticostriatal circuits. Opto- and chemo-genetic strategies will be used to test whether enhancing cortical or striatal cholinergic neurotransmission can reduce fall propensity in the ?Dual Lesion? (DL) rodent model of PD falls. Project II will employ the cholinergic PET ligand [18F]FEOBV in PD subjects to test the hypothesis that specific regional patterns of cholinergic dysfunction associate with distinct PD gait abnormalities, including falls and freezing of gait. Combined with Project I, this work has the potential to establish striatal cholinergic interneurons as an essential mediator of PD gait dysfunction. Project III will assess occipital cortical cholinergic denervation in PD subjects as an early, pathologic biomarker of later gait and cognitive decline. Projects II and III will take advantage of the uniquely valuable PD subject cohort established during the original funding period, and together constitute a first step toward the development of novel PD stratification tools. The U-M Udall Center will collaborate with members of the Pacific and University of Rochester Udall Centers, and be supported by Administrative, Clinical Resource, Neuroimaging Resource and Biostatistics and Data Management Cores. The Administrative Core is strongly committed to and will direct education of PD researchers, PD patients, and their families. Together, our innovative approaches will advance the goal of the NINDS Udall Centers of Excellence program to ?define the causes of and discover improved treatments for PD.? No other current Udall Center is focused on gait and postural abnormalities in PD, on cholinergic deficits, or on use of a pathological biomarker to define PD subgroups. The proposed U-M Udall Center will continue to play a unique and important role within the Udall Centers program.
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2020 |
Albin, Roger L |
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.) |
Vigor and the Ldr in Parkinson Disease @ University of Michigan At Ann Arbor
Abstract Dopamine replacement therapy (DRT) is the standard and very effective symptomatic treatment for early to moderate Parkinson disease (PD). The most important DRT component is the Long Duration Response (LDR), a pharmacodynamic effect that builds up over the course of weeks. DRT actions are poorly understood and the basis of the LDR is unknown. As the LDR wanes in advancing disease, PD patients develop troublesome motor fluctuations and increasing disability. LDR kinetics suggest long-term plastic changes in striatal function. Studies of striatal dopamine actions indicate that striatal dopaminergic neurotransmission regulates ?vigor;? modulation of the velocity, amplitude, force, or frequency of movements. Vigor is closely allied with the concept that striatal dopaminergic neurotransmission mediates motivation; assessment of act utility and appropriate scaling of actions to perceived rewards. Recent theoretical and experimental results suggest that tonic striatal dopamine signaling is a key determinant of movement vigor. Convergent clinical pharmacologic and experimental data lead to a strong hypothesis that the LDR results from chronic DRT partially restoring movement vigor. This model of the LDR requires stable ?records? of action values. Recent non-human primate work on saccadic eye movement vigor indicates the existence of striatal dopaminergic neurotransmission stably encoding motor behavior values for prolonged periods ? a potential mechanism for the LDR. Prior experiments examining vigor in PD did not take the LDR into account, resulting in incomplete examinations of the role of vigor deficits in PD. Our long-term goal is to understand the clinically relevant actions of DRT. The primary objective of our proposal is to test the hypothesis that the LDR results from partial restoration of normal movement vigor-motivation. Our secondary objective is to evaluate a potential mechanism underlying the LDR. The rationale for these experiments is that better understanding of the LDR, a clinically crucial component of DRT action, will lead to improved symptomatic therapy. We will study recently diagnosed PD subjects. All subjects will undergo standard evaluations of clinical, cognitive, and motivational features. Subjects will perform incentive motivation tasks assessing movement vigor ? motivation coupling to assess our primary hypothesis. A task assessing saccadic eye movement vigor in response to stable value signals will be employed to evaluate our secondary hypothesis. They will perform all tasks before and after LDR induction in both the ?practical off? and post-acute treatment states. Validation of our hypotheses would have considerable impact by identifying the functional process underlying the LDR and providing information for uncovering the mechanisms of the LDR. This would facilitate research into LDR mechanisms, provide a rational basis for developing valid animal models of the LDR, and open a new path towards improved symptomatic management of PD.
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2021 |
Albin, Roger L |
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. |
Project Iii: Cingulo-Opercular Task Control Network Cholinergic Dysfunction in Pd @ University of Michigan At Ann Arbor
PROJECT III: SUMMARY/ABSTRACT Cognitive deficits are a morbid dopamine replacement therapy-refractory feature of Parkinson disease (PD). The pathophysiology of PD-related cognitive deficits is complex, likely involving interacting and variable impairments of several brain systems, particularly in early to moderate disease. Incidence and natural history of PD cognitive deficits is heterogeneous. Understanding the pathophysiologies of PD cognitive impairments is essential for development of personalized therapies. PD heterogeneity is a major obstacle to effective clinical research. Identifying PD subgroups will enhance discovery of useful interventions through subgroup specific or stratified clinical trials, identify biomarkers, improve prognosis assessment in clinical care, and assist etiopathogenic research. Some of the ?highest priority recommendations? of the NINDS PD 2014 Research Report call for research to understand the pathophysiology of cognitive impairments and for PD subgroup identification. The U-M Udall Center established a deeply phenotyped PD cohort imaged with the vesicular acetylcholine transporter PET ligand [18F]FEOBV, revealing heterogeneous cholinergic deficits. Cholinergic terminal deficits in Cingulo-Opercular Task Control network (COTC) nodes ? Anterior Cingulate and Insular Cortices (AC-I) ? correlate with both domain specific and global cognitive deficits. An important component of the Attentional-Motor Interface (AMI; Overall Component), the COTC subserves tonic attention, coordinating network activities across different cognitive domains. Preliminary analysis suggests that early COTC node (AC- I) cholinergic deficits are a subgroup defining-feature in PD, predicting more rapid cognitive decline. The central hypothesis of Project III is that early COTC node (AC-I) cholinergic denervation contributes significantly to cognitive impairment in early to moderate PD and identifies a PD subgroup with accelerated cognitive decline. In addition to our established Udall subject cohort, we have access to a separate cohort of incident PD subjects through collaboration with the University of Groningen, deeply phenotyped and imaged with [18F]FEOBV PET, for rigorous experimental replication and validation of our primary hypothesis. We will correlate early COTC node (AC-I) cholinergic denervation with domain-specific and general measures of cognitive function. In a prospective analyses, we will determine if early COTC node (AC-I) cholinergic denervation predicts more rapid cognitive decline. In an integrated analysis with Project I, we will determine if COTC node (AC-I) cholinergic denervation is associated with Freezing of Gait (FoG). In exploratory analyses, we will assess if more accessible MRI or other measures correlate with COTC node (AC-I) cholinergic denervation, identifying potential, accessible biomarkers of COTC node (AC-I) cholinergic denervation. Project III will identify an important substrate of PD cognitive impairment and identify a PD subgroup with a more aggressive natural history - a ?malignant hypocholinergic disease phenotype.? These results will identify potential targets for therapeutic interventions and biomarker development.
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2021 |
Albin, Roger L |
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. |
Core a: Administrative Core @ University of Michigan At Ann Arbor
CORE A: SUMMARY/ABSTRACT The Administrative Core (AC) will coordinate all scientific, administrative, outreach, and educational activities of the U-M Udall Center. The central objective of the AC is to facilitate realization of the scientific and educational goals of the U-M Udall Center. The Executive Committee (EC) of the AC will be the ultimate decision-making body for all Center administrative, scientific, and educational policies. The EC, composed of all Project and Core Leads, including the Catalyst Project Lead, will be assisted by Internal and External Advisory Committees, which will review Center activities annually. Beyond its oversight of scientific, administrative, and fiscal matters, the AC will be responsible for community outreach and trainee education. The AC will work to publicize Center goals and discoveries. The principal vehicles for communicating this information will be the U-M Udall website and annual research participant education symposia. The AC will supervise enhancement of the scientific training of all Center trainees, each of whom will work under the supervision of a Project Leader and have their progress reviewed annually by the EC. The AC will provide enhanced mentorship for the Catalyst Project Lead and oversee the training of a Udall Research Fellow.
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