Many fundamental cellular processes are affected by epigenetic modulation, and in recent years it has become evident that chromatin-based epigenetic mechanisms underlie important aspects of the aging process. However, despite the fact that age is a prominent risk factor in neurodegenerative disease (ND), there is remarkably little information on the role of epigenetic alterations in mechanisms of ND such as Alzheimer's disease (AD), Parkinson's dementia (PD), frontotemporal degeneration (FTLD) or amyotrophic lateral sclerosis (ALS). We believe that a detailed biological, mechanistic and molecular understanding of the epigenetic factors that are altered in human ND holds promise for an improved understanding of disease pathogenesis and for the development of novel therapeutic interventions. The goals of this Project are to: (1) investigate whether major epigenetic modifications (histone post-translational modifications) change in the context of different NDs using an extensive bank of human samples available from the Penn Center for Neurodegenerative Disease Research (CNDR), (2) use our model systems to discover new epigenetic modifications that underlie ND disease, and (3) test the relevance of novel changes seen in human ND using models of ND. The proposed studies of this multiple-PI and co-Investigator effort will leverage complementary and intersecting interests from our laboratories concerning epigenetics and aging (Berger, Bonini, Johnson), ND (Bonini, Torres and Trojanowski), and the generation and bioinformatic analysis of genome-wide data obtained by chromatin immunoprecipitation followed by second generation sequencing (Gregory, Wang, Berger). The application of our combined expertise to the analysis of the rich collection of CNDR ND brain samples will launch a major new effort in the field of epigenetics in ND. In the broader scientific and medical communities, this effort will promote discoveries of epigenetic mechanisms of ND to provide the foundation for new insights and novel clinical approaches to treat ND. )

Public Health Relevance

Advancing age is a major risk factor for neurodegenerative diseases like Alzheimer's disease and Parkinson's dementia, diseases that exact enormous personal suffering and costs to society, yet little is known about precisely how aging contributes to these diseases. Recently it has become evident that changes in the structure called chromatin, which organizes our genes and regulates their activity, underlie key aspects of the aging process. We will investigate the precise nature of chromatin changes in brains from people with neurodegenerative diseases, and test how these changes interfere with normal function, thus providing a basis for new classes of diagnostics and therapies that will improve human well-being. )

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS078283-03S1
Application #
8889810
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Corriveau, Roderick A
Project Start
2012-03-01
Project End
2017-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Bonini, Nancy M; Berger, Shelley L (2017) The Sustained Impact of Model Organisms-in Genetics and Epigenetics. Genetics 205:1-4
Bonini, Nancy M; Lee, Edward B; Wasco, Wilma et al. (2017) Editorial overview: Molecular & genetic basis of disease. Curr Opin Genet Dev 44:iv-vi
Cohen, Justin; Torres, Claudio (2017) HIV-associated cellular senescence: A contributor to accelerated aging. Ageing Res Rev 36:117-124
Cohen, Justin; D'Agostino, Luca; Wilson, Joel et al. (2017) Astrocyte Senescence and Metabolic Changes in Response to HIV Antiretroviral Therapy Drugs. Front Aging Neurosci 9:281
Chen, Natalie C; Partridge, Andrea T; Sell, Christian et al. (2017) Fate of microglia during HIV-1 infection: From activation to senescence? Glia 65:431-446
Sen, Payel; Shah, Parisha P; Nativio, Raffaella et al. (2016) Epigenetic Mechanisms of Longevity and Aging. Cell 166:822-839
Crowe, Elizabeth P; Tuzer, Ferit; Gregory, Brian D et al. (2016) Changes in the Transcriptome of Human Astrocytes Accompanying Oxidative Stress-Induced Senescence. Front Aging Neurosci 8:208
Maciel-BarĂ³n, L A; Morales-Rosales, S L; Aquino-Cruz, A A et al. (2016) Senescence associated secretory phenotype profile from primary lung mice fibroblasts depends on the senescence induction stimuli. Age (Dordr) 38:26
Perrimon, Norbert; Bonini, Nancy M; Dhillon, Paraminder (2016) Fruit flies on the front line: the translational impact of Drosophila. Dis Model Mech 9:229-31

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