权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

An in vivo multiplex model to study gene-environment interaction in Parkinson's Disease

研究帕金森病基因与环境相互作用的体内多重模型

基本信息

批准号：
10843389
负责人：
Souvarish Sarkar
金额：
$ 24.9万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10843389
关键词：
Actin-Binding Protein Actins Adult Automobile Driving Autopsy Binding Proteins Biochemical Biological Assay Biological Models Brain Caffeine Candidate Disease Gene Cell model Cells Clinical Complex Data Disease Drosophila genus Drug Targeting Environmental Risk Factor Epidemiology Etiology Exposure to Gene Modified Genes Genetic Genetic Screening Guanosine Triphosphate Phosphohydrolases Human Idiopathic Parkinson Disease In Vitro Induced pluripotent stem cell derived neurons LRRK2 gene Laboratories Lead Link Mel B Mentors Methods Modeling Molecular Nerve Degeneration Neurodegenerative Disorders Neurons Neurotoxins Nicotine Parkinson Disease Pathogenesis Pathologic Pathology Pathway interactions Patients Pesticides Pharmaceutical Preparations Phosphotransferases Play Protein Kinase Proteomics Risk Risk Factors Rodent Model Role Rotenone Series System Techniques Training Tyrosine 3-Monooxygenase Universities alpha synuclein disorder risk dopaminergic neuron druggable target epidemiology study experimental study fly gene environment interaction genetic risk factor genome wide association study in vivo induced pluripotent stem cell inhibitor medical schools mitochondrial dysfunction mouse model mutant neurotoxic neurotoxicity neurotoxicology novel overexpression personalized medicine pharmacologic precision drugs prevent public health relevance stem cell model superresolution microscopy symposium synuclein synucleinopathy therapeutic target tool

项目摘要

Project Summary/Abstract Parkinson's disease (PD) is a progressive neurodegenerative disorder that is characterized by α-synuclein-rich neuronal inclusions. Recent genome-wide associated studies (GWAS) and epidemiological studies have identified multiple candidate genes and environmental factors, respectively, which can modify PD risk. Studying polygenic interactions with environmental factors has been difficult due to the lack of a model system. However, studies have hinted at a complex relationship between α-synuclein, the genetic risk factors, and environmental factors. In our preliminary data, we have established a multiplex model using the Drosophila model of PD. In this model, we express human α-synuclein, simultaneously modify GWAS candidate genes in neurons, and expose adult flies to rotenone. Using a combination of scalable techniques in this model, we identified novel interactions among α-synuclein, environmental factors, and GWAS genes. The overarching hypothesis is a multiplex model, in combination with iPSC-derived neurons, can be used to identify and study the mechanism of novel gene-environment interactions. Further, this model system will identify potential drug targets that can modify the gene-environment interactions. In Aim 1, a series of experiments, including super-resolution microscopy and iPSC-derived tyrosine hydroxylase (TH) neurons, will be performed to characterize the interaction among LRRK2, rotenone, and α-synuclein, which was identified using the multiplex model. These experiments will be performed in the laboratory of primary mentor Mel B. Feany. Aim 2 will involve understanding the mechanism of interactions among LRRK2, rotenone, and α-synuclein. Previous studies and preliminary experiments have shown that actin hyperstabilization plays a central role in regulating neurotoxicity. Herein biochemical, immunohistological, and neurotoxicity assays will be performed in Drosophila and iPSC-derived TH neurons (obtained disease-causing LRRK2-G2019S and protective LRRK2-R1398H iPSCs) to study the role of actin dynamics in regulating this gene-environment interaction. These experiments will be performed in Dr. Feany's lab. In the independent R00 section, a druggable target that can modify the interaction among LRRK2, rotenone, and α-synuclein will be identified. Further, we will screen for other PD-related neurotoxicants that interact with LRRK2 and α-synuclein through actin hyperstabilization. We will genetically and pharmacologically inhibit MRCKα, a kinase that can regulate actin hyperstabilization, in flies, iPSC-derived neurons, and a mouse model. My neurotoxicology and neurodegeneration training will be facilitated by didactic courses and participation in Clinical Pathological conferences at Harvard Medical School and the Exposome boot camp at Columbia University organized by co-mentor Gary Miller. This project may elucidate a novel model system that can be used to identify and study the mechanism of gene-environment interactions. The training that I undertake will enable me to transition to independence and lead a laboratory investigating the molecular mechanisms of gene-environment interactions in neurodegenerative disorders.

项目总结/文摘