Tiered Mentoring Project  Use of novel autophagic modulating compounds in neurodegenerative disease Dr. Matthew A. Smith, Assistant Professor of Pharmaceutical Sciences at NEOMED

Note: Any student chosen for this project will be responsible for providing their own transportation to Northeast Ohio Medical University (NEOMED).

Autophagy in neurons is closely tied to pre-degenerative axonal and synaptic alterations that drive the pathophysiology underlying neurodegenerative disease. Growing genetic and biochemical evidence implicates the dysfunction of endosomal–lysosomal and autophagic lysosomal pathways during the pathogenesis of many neurodegenerative diseases, including Alzheimer’s Disease (AD). Despite an unclear understanding of the interplay between autophagy and inflammatory mechanisms on axon and synapse function and cell death, emerging evidence has shown that reducing the accumulation of intracellular aggregate-prone proteins through autophagy enhancement via modulation of mTOR‐dependent or ‐independent pathways could effectively ameliorate neuropathology and neurodegeneration. As potential therapeutics for neurodegeneration continue to fail in clinical trials at alarming rates, there are still no disease-modifying treatments available to slow or stop the progressively damaging course of neuron dysfunction and loss in AD.

The long-term goal of this study is to investigate the potential therapeutic benefit of BM-3109, a novel small molecule mTOR inhibitor, in Alzheimer's Disease.  BM-3109’s low cytotoxicity profile and innovative molecular design enable it to act on both the autophagy and inflammatory signaling pathways allowing it to harness two powerful mechanisms, both of which play a critical role in the pathophysiological progression of AD. To accomplish this task, we will chronically administer BM-3109 intravenously to 3xTg-AD mice stratified across two age groups representing early and late disease stages. We will use a combination of epifluorescent microscopy and in vivo physiological techniques to determine the impact of BM-3109 on well-described prodromal disease outcomes. This project is part of an academic-industry collaboration between the Smith Lab and BioMendics, LLC, the developers and patent holder of BM-3109.

Student Duties and Expectations:

Students will be able to be involved in every aspect of this project including but not limited to drug administration, tissue collection, performing histological assays and microscopy, electrophysiological and behavioral testing, and data analysis. Students desiring a full well-rounded experience should be able to commit a minimum of 2-days a week.