Gastric dopaminergic signaling and mucosal injury in Parkinson's disease

PROJECT SUMMARY/ABSTRACT Parkinson’s disease, a neurodegenerative disorder characterized by central depletion of dopaminergic neurons, affects over 1 million Americans. Treatment options in PD are limited, aimed at motor complications, with no targeted therapies directed at widespread gastrointestinal (GI) dysfunction that precedes CNS symptoms. Indeed, a gut-first hypothesis of PD posits that certain—as yet unknown—pathologic triggers occur first in the gut before disease propagation to the brain. The hypothesis is bolstered by evidence demonstrating GI symptoms like gastroparesis and upper GI mucosal injury (MuI) are associated with an elevated risk of subsequent PD. While the mainstay of PD treatment is exogenous levodopa, which is metabolized to dopamine by L-amino acid decarboxylase (AADC), in 80% of patients, its effect on motor symptoms is eventually fluctuating and unpredictable, a major obstacle in the field. Prior research suggests levodopa’s inconsistent effects may be due to variable GI uptake, however, to date, there are no studies investigating the consequences of GI dopamine metabolism and signaling on levodopa pharmacokinetics in PD—nor has there been elucidation of what inciting pathologic GI disturbances may induce these changes. Understanding these mechanisms, therefore, is a critical unmet need. My central hypothesis is that AADC expression determines pathophysiological sequelae in PD, including reduced levodopa bioavailability, MuI, delayed gastric emptying, and other associated symptoms. To test this hypothesis, I will examine dopamine signaling pathways in gastric mucosal biopsies through quantitative immunohistochemistry, ELISA and spatial transcriptomics of otherwise healthy controls and PD patients and correlate them with gastric emptying, gastrointestinal symptoms and MuI (Aim 1). Next, I will perform a pharmacokinetics trial to study circulating levodopa bioavailability in patients with and without upregulated gastric AADC and correlate with motor impairment (Aim 2). I expect that this work will allow us to identify key pathways involved in pathophysiological gut disturbances in PD and how those changes may drive gastroparesis and motor symptoms. Such results have the potential to not only improve morbidity, but to serve as a foundation for early PD recognition and intervention in the gut that may prove applicable to other neurodegenerative diseases. Further, through the proposed work, as well as a formal didactic curriculum, the candidate will gain training in the fields of mucosal biology, enteric neuroscience, spatial transcriptomics and pharmacology. This career development plan will enable to candidate to achieve her long-term goals of a) developing a simple biomarker for predicting gastrointestinal sequelae of PD, personalizing treatment and targeting early intervention and b) becoming an independently-funded clinical-investigator in neurogastroenterology. The candidate will conduct this work in the rich, collaborative environment of Beth Israel Deaconess Medical Center and Harvard Medical School, supervised by a world-class mentorship team and research advisory committee.