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.