Pilot Grants Awarded to Spur Parkinson's Disease Research

Over the course of the next five years, the goal is to build a solid foundation and position the Center to obtain national distinction. Under the auspices of the Institute for Integration of Medicine & Science (IIMS), the Center solicited the first round of pilot proposals this past spring.

Out of ten proposals submitted in the inaugural year, five projects were selected to receive a total of $215,000. The early phase projects will generate preliminary data laying the foundation to secure competitive external grants.  Each finalist proposed to approach Parkinson’s disease (PD) from a different perspective - a tactic that aligns with the Center’s strategic goal of simultaneously cultivating multiple promising research avenues while fostering career development and inter-disciplinary collaborations across the institution.

PD is a complex disorder with a multi-factorial etiology. Evidence suggests that several mechanisms are pertinent to dopaminergic neuron degeneration in the part of the brain known as substantia nigra – such as, overabundance of reactive oxygen species, abnormal protein folding/aggregation, perturbed mitochondrial activity, endoplasmic reticulum (ER) stress, imbalanced calcium homeostasis, and induction of apoptosis. Two of the selected proposals are aimed at understanding cellular mechanisms underlying PD neurodegeneration or neuroprotection.

• Dr. Jean Chrisostome Bopassa’s project focuses on mitochondrial dysfunction and subsequent respiratory chain deficits. The PD-related proteins parkin and PINK1 promote the destruction of damaged mitochondria, but the mechanism for this damage is poorly understood. By contrast, the protein mitofilin maintains mitochondrial structure and function, and mitofilin knockdown increases PD-like mitochondrial dysfunction and apoptosis. Dr. Bopassa’s team will develop a novel mouse model selectively lacking mitofilin in dopaminergic neurons. This tool will provide a means to determine the impact of mitofilin regulation in neurodegenerative diseases like PD.
• Dr. Brij Singh’s laboratory examines the contribution of disrupted calcium homeostasis to PD pathology. Among other cellular functions, calcium is transported and stored in the endoplasmic reticulum (ER) where it is required for proper protein synthesis and folding. In all cells, calcium release from the ER opens ion channels that replenish ER calcium. In dopaminergic neurons, TRPC1 (transient receptor potential canonical 1) is the ion channel responsible for this function. As prior animal and cell culture models of PD exhibit impaired TRPC1 function, Dr. Singh will investigate the pathways of TRPC1-mediated neuroprotection,

Available treatments for PD (dopamine agonists) can relieve motor symptoms, but they do not halt disease progression and their long-term use leads to debilitating side effects and decreased efficacy. Most drug development efforts are focusing on neuroprotective and neurorestorative strategies, and potential cures. Three pilot projects focused on novel therapeutic interventions:

• Using national electronic health records (Veterans Administration Corporate Data Warehouse) and animal models, Dr. Amrita Kamat’s team will study whether β2-adrenergic receptor agonists like formoterol and albuterol, currently approved for treating asthma, can be re-purposed as new cost-effective therapeutic options to delay onset and slow PD progression. This research intends to replicate epidemiologic evidence from a Norwegian cohort study that Dr. Kamat carried out on a larger and more diverse population from the Veterans Administration. In tandem with the pre-clinical study, the Kamat laboratory will also test formoterol in animal models.

• Dr. Senlin Li’s team will utilize glial cell-derived neurotropic factor (GDNF) for the neuroprotection of dopaminergic neurons. Dr. Li believes that previous clinical trials of brain stem injections failed to deliver adequate GDNF to the cellular targets. He proposes a cell-based delivery system whereby transplanted hematopoietic stem cells expressing GDNF generate macrophages/microglia that home to areas of neurodegeneration. Using this technology, Dr. Li has successfully ameliorated motor and non-motor Parkinsonian symptoms in two mouse models. The current project will test the approach in a newer alpha-synuclein (α-syn) transgenic mouse model that more closely mimics PD pathophysiology.   
• Dr. Biju Chandu will study inhibitors of the Nox family of NADPH oxidases, which comprise enzymatic complexes likely involved in the oxidative stress and neuroinflammation observed in PD. The team is using a transgenic mouse model of PD to evaluate the expression patterns of various catalytic subunits of NADPH oxidase in PD-related brain regions, and to further characterize the poorly understood relationship between Nox expression and accumulation of α-synuclein protein. This project will lay the foundation for studying the potential neuroprotective effects of Nox inhibitors in PD.