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Project: 1
Development and Pharmacological Characterization of Mechanistically Distinct NMDA Receptor Allosteric Modulators
Most pharmacological agents that are binding at NMDA receptor agonist binding domain (ABD) cleft are weakly selective for the GluN2 subunit of interest. Therefore we are currently targeting the less conservative GluN1/2 ABD interface to design subtype-selective positive and negative allosteric modulators. Two electrode voltage clamp and patch-clamp electrophysiology techniques are used to study the NMDA receptor function. Computational modeling, docking and molecular dynamics simulation techniques are used to predict potential drug targets and ligand designing.
Project: 2
Improving Brain Metabolic Waste Clearance in an Animal Model of Alzheimer’s Disease by Cranial Osteopathic Manipulation
A novel "Mechanoceutics TM" Treatment Strategy for Alzheimer’s Disease
Studying potential use of mild mechanical pressure for the treatment of Alzheimer’s disease. This idea was conceived based on knowledge about the existence of brain lymphatic vessels and the capability of cranial osteopathic manipulation (COM) to improve fluid circulation in the brain. COM-treated eighteen-month-old rats exhibit improvement in spatial learning and memory, reduction in Aβ plaques, and changes in substrates associated with CNS fluid clearance. Currently, continuing this work using a transgenic rat (TgF344-AD) model of Alzheimer’s disease.
There are numerous animal models available for Alzheimer’s disease. The most commonly used models are transgenic animals that overexpress amyloid precursor protein (APP), a precursor for Aβ that accumulates in the brain and initiates Alzheimer’s disease pathology. At toxic levels, such amyloid accumulation causes characteristics of Alzheimer’s disease, evidenced by defects in learning and memory. We use a transgenic rat (TgF344-AD) model for Alzheimer’s disease that mimics age-dependent cognitive decline and is more translatable to humans compared to other models. These animals express the human amyloid precursor protein (APP) gene with two Swedish mutations (K595N & M596L) and the exon-9 deleted presenilin-1 gene.
Following are the techniques used for this study:
Spatial learning and memory assay.
Positron emission tomography (PET) imaging for Aβ plaques using the FDA-approved radiotracer, Florbetapir F18 injection (Amyvid).
Biochemical analysis of brain tissue samples.
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