This grant builds upon the research from a prior grant: Characterization of a Novel Strategy to Target LRRK2 and Its Downstream Signaling Pathway
Study Rationale:
Genetic mutations in LRRK2 are linked to familial Parkinson’s, however, there are currently no clinically approved inhibitors for LRRK2. In this study, we will develop and characterize novel types of inhibitor compounds that either target LRRK2 itself or target a key downstream signaling pathway that is upregulated by LRRK2. Together, these tools will be used to investigate the mechanism and function of LRRK2 in cells.
Hypothesis:
The compounds made in this study will be used to investigate the mechanism and function of LRRK2 in cells and explore the hypothesis that disrupting how LRRK2 becomes active, or targeting a key signaling pathway that is upregulated in the disease state, may serve as effective strategies to block altered signaling in Parkinson’s patients.
Study Design:
As a strategy to disrupt LRRK2 hyperactivity as seen in Parkinson’s, new compounds will be designed that block LRRK2 function or it’s downstream signaling. These compounds will undergo a variety of assays to measure their effectiveness at downregulating the high levels of LRRK2 activity and altered signaling that are found in the disease state.
Impact on Diagnosis/Treatment of Parkinson’s disease:
This study will explore new targeting strategies that aim to block the activity of LRRK2, which is a key underlying mechanism for familial Parkinson’s disease progression. The significance of this study is that it will validate the notion of new targeting sites and represents a novel strategy for the development of new Parkinson’s therapeutics.
Next Steps for Development:
The inhibitors developed in this work may serve as templates for the development of completely novel therapeutic agents in Parkinson’s. Future preclinical studies will also establish the efficacy and feasibility of this approach.