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Investigating environmental and gene-environment contributors to Parkinson's disease risk by coupling quantitative environmental exposure data to iPSC modeling

Award Number: K08ES034822
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

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PROJECT SUMMARY Parkinson's Disease (PD) is considered a “man-made” pandemic, triggered in part by industrialization that has entailed increased production needs and exposure to toxicants resulting from that growth. Despite the discovery of important genetic risk factors, a substantial amount of etiologic risk for idiopathic PD is environmental, with pesticide exposure being a clear and documented risk factor. As a result, understanding the interaction between genetic drivers and environmental risk factors has significant potential to inform etiology and treatment of PD. This project will investigate how environmental factors, specifically pesticides, influence the development of PD at the level of effects on midbrain dopaminergic (mDA) neurons, a cell type whose loss is the hallmark of PD pathology. The work is informed by a paradigm in which highly quantitative pesticide exposure data from a large PD cohort in California is linked to a screening platform using patient stem cell (iPSC)-derived mDA neurons. Fifty-three pesticides were linked to PD with this method and ten proved directly toxic to mDA neurons. The proposed work will: (1) deeply dissect mechanisms of mDA neuron toxicity for top hits with a focus on mitochondrial and cytoskeletal consequences of trifluralin exposure; (2) explore the role of glia in modulating toxicity using a triculture approach to ask how other PD-associated pesticides alter astrocyte and microglial biology to influence mDA neuron pathology; and (3) use population-level modeling of sporadic PD in a dish to build a platform that will stratify cells from ~100 donors functionally based on responses to pesticides and then use computational methods to reconstruct which cell lines are disproportionately affected. This will identify shared phenotypes among genetically disparate samples. The career development plan is designed to support the candidate's goal of becoming an independent investigator at an academic medical center, treating PD patients in clinic while concurrently leading a research team studying their disease. A strong mentorship and collaborative team in a vibrant research environment is led by a supportive neurology chairperson (Batchelor), outstanding physician scientists with expertise spanning from neurodegeneration (Khurana, Selkoe) to public health and epidemiology (Ritz) to translational neuroscience (Rubin, Studer, Powell). This mentorship team, along with extensive research training and relevant coursework, will position the candidate for success. The institutional resources available through Brigham and Women's Hospital, and Harvard University will support the candidate's career in an environment that makes high impact contributions and collaborative endeavors achievable. The successful execution of this proposal will position the candidate along a path for an independent career as a physician scientist studying the interplay of gene-environment interactions in PD to better treat and prevent this disease.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $209,607 )
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Environmental Health	000	3	11/18/2024	NON-COMPETING CONTINUATION	$209,607
														Subtotal = $209,607

Issue Date FY: 2024 ( Subtotal = $208,423 )
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Environmental Health	000	2	11/15/2023	NON-COMPETING CONTINUATION	$208,423
														Subtotal = $208,423

Issue Date FY: 2023 ( Subtotal = $197,177 )
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Environmental Health	000	1	11/24/2022	NEW	$197,177
														Subtotal = $197,177

Grand Total All Awards = $615,207

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Investigating environmental and gene-environment contributors to Parkinson's disease risk by coupling quantitative environmental exposure data to iPSC modeling

Award Number: K08ES034822

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

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