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ApoE Regulation of Alpha-Synuclein Pathology in Parkinson Disease Dementia

ApoE 对帕金森病痴呆中 α-突触核蛋白病理学的调节

基本信息

批准号：
10216360
负责人：
Albert A Davis
金额：
$ 16.53万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10216360
关键词：
Affect Age-Months Alleles Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid Fibrils Amyloid beta-Protein Apolipoprotein E Astrocytes Attenuated Award Basic Science Binding Biochemical Biosensor Brain Brain region Caregivers Cell Line Cells Clinical Co-Immunoprecipitations Code Complement Corpus striatum structure Data Dementia Dementia with Lewy Bodies Development Development Plans Disease Doctor of Philosophy Ensure Environment Event Exposure to Faculty Fluorescence Genes Genetic study Gliosis Goals Growth Health Human Human Genetics Idiopathic Parkinson Disease In Vitro Individual Injections International K-Series Research Career Programs Kinetics Knock-in Knock-in Mouse Knowledge Laboratories Learning Lewy Bodies Life Lipids Literature Measures Mentors Mentorship Modification Molecular Molecular Chaperones Molecular Conformation Monitor Morbidity - disease rate Movement Disorders Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neurologist Neurology Neuronal Dysfunction Neurons Nursing Homes Parkinson Disease Parkinson&apos s Dementia Pathogenesis Pathologic Pathology Patients Phase Physicians Physiological Positioning Attribute Process Protein Conformation Protein Isoforms Proteins Regulation Reporting Research Research Personnel Research Training Risk Risk Factors Role SNCA gene Scientist Structure Surface Plasmon Resonance Techniques Testing Toxic effect Training Transgenic Mice Translating Work alpha synuclein apolipoprotein E-3 apolipoprotein E-4 beta amyloid pathology beta pleated sheet brain cell career career development cell type comorbidity cost design disability effective therapy experience experimental study genetic risk factor in vivo meetings monomer neuron loss novel prevent protein aggregation recruit responsible research conduct role model skills tetramethylrhodamine therapeutic target

项目摘要

7. Project Summary/Abstract The goal of this mentored career development award is to facilitate the candidate's transition to independence as a physician-scientist studying molecular mechanisms of neurodegeneration. The candidate is an MD/PhD neurologist with a background in neurodegenerative disease research. The award will help the candidate achieve his short-term goal, to gain research experience in the molecular pathogenesis of Parkinson disease and dementia and facilitate his transition to an investigator with an independent laboratory. The award will also help position the candidate to achieve his long-term goal of becoming a successful and productive physician- scientist and a leader in academic neurology. The environment in which the proposed research will be conducted is outstanding. The candidate's primary mentor, Dr. David Holtzman, is an internationally respected scientist and neurologist with a proven track record of excellence in training junior faculty. The candidate's career development plan also includes structured mentorship from multiple physician-scientists at all stages of seniority and exposure to a rich and supportive faculty, ensuring that the candidate has role models along the full spectrum of the career trajectory. Didactic learning, presentation of work at scientific meetings, and rigorous training in the responsible conduct of research will ensure a balanced development. The proposed research will examine the role of apolipoprotein E (apoE) in regulating the aggregation and pathological spread of alpha synuclein (αSyn), a protein implicated in Parkinson disease (PD), Parkinson disease dementia (PDD), and dementia with Lewy bodies (DLB). The aggregation of αSyn from its native monomer form into oligomers is thought to be toxic and to contribute to neuronal dysfunction. This process is regulated by other proteins including chaperone proteins. Several genetic studies point to the APOE ε4 allele, the strongest genetic risk factor for Alzheimer disease, as a risk factor for developing dementia in PD as well. APOE is and is known to regulate amyloid-beta (Aβ) pathology and individuals with PD often have comorbid αSyn and Aβ pathology, but importantly, the risk effect of APOE in PDD and DLB appears to be independent of Aβ pathology. The goal of this project is to test the hypothesis that apoE isoforms differentially regulate αSyn aggregation by stabilizing a harmful oligomeric intermediate. A secondary hypothesis is that apoE regulates the propagation of pathologic conformations of αSyn from cell to cell in vivo. The proposed experiments are designed to elucidate a potential novel relationship between apoE and αSyn, with the ultimate goal of identifying therapeutic targets that can be leveraged to treat diseases caused by pathologic aggregation of αSyn. This career development award is an ideal mechanism to provide the candidate with valuable research training which will complement his clinical focus in movement disorders and will help develop a skill set for translating basic science discoveries into effective therapies for patients with neurodegenerative diseases.

7. 项目总结/文摘

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Intercellular Spread of Protein Aggregates in Neurodegenerative Disease.

DOI：
10.1146/annurev-cellbio-100617-062636
发表时间：
2018-10-06
期刊：
Annual review of cell and developmental biology
影响因子：
11.3
作者：
Davis AA;Leyns CEG;Holtzman DM
通讯作者：
Holtzman DM

HtrA1 prevents and reverses α-synuclein aggregation, rendering it non-toxic and seeding incompetent.

HtrA1 防止并逆转 α-突触核蛋白聚集，使其无毒且无法播种。

DOI：
10.21203/rs.3.rs-2570571/v1
发表时间：
2023
期刊：
Research square
影响因子：
0
作者：
Chen,Sheng;Puri,Anuradhika;Bell,Braxton;Fritsche,Joseph;Palacios,Hector;Balch,Maurie;Sprunger,Macy;Howard,Matthew;Patterson,Jessica;Patti,Gary;Davis,Albert;Jackrel,Meredith
通讯作者：
Jackrel,Meredith

A Systematic Review and Case Series of Ziprasidone for Psychosis in Parkinson's Disease.

齐拉西酮治疗帕金森病精神病的系统回顾和病例系列。

DOI：
10.3233/jpd-181448
发表时间：
2019
期刊：
Journal of Parkinson's disease
影响因子：
0
作者：
Younce,JohnR;Davis,AlbertA;Black,KevinJ
通讯作者：
Black,KevinJ

HTRA1 disaggregates α-synuclein amyloid fibrils and converts them into non-toxic and seeding incompetent species.

HTRA1 分解 α-突触核蛋白淀粉样原纤维，并将其转化为无毒和播种无能的物种。

DOI：
10.1038/s41467-024-46538-8
发表时间：
2024
期刊：
Nature communications
影响因子：
16.6
作者：
Chen,Sheng;Puri,Anuradhika;Bell,Braxton;Fritsche,Joseph;Palacios,HectorH;Balch,Maurie;Sprunger,MacyL;Howard,MatthewK;Ryan,JeremyJ;Haines,JessicaN;Patti,GaryJ;Davis,AlbertA;Jackrel,MeredithE
通讯作者：
Jackrel,MeredithE

MAPT R406W increases tau T217 phosphorylation in absence of amyloid pathology.

DOI：
10.1002/acn3.51435
发表时间：
2021-09
期刊：
Annals of clinical and translational neurology
影响因子：
5.3
作者：
Sato C;Mallipeddi N;Ghoshal N;Wright BA;Day GS;Davis AA;Kim AH;Zipfel GJ;Bateman RJ;Gabelle A;Barthélemy NR
通讯作者：
Barthélemy NR