Discovery and Development of Chemical Probes to Elucidate MS4A Protein Function

2020

Genome-wide association studies (GWAS) in Alzheimer’s disease (AD) suggest that studying the immune system of the brain may provide insights into disease resilience, onset and progression. Many think the brain immune system is likely the next target for drugs to treat this intractable disease. Currently though, there are huge knowledge gaps that exist in our understanding of brain immune system function in AD and its relationships to classic AD pathology (e.g., amyloid plaques and neurofibrillary tangles). In many cases, the basic tools—including chemical probes—needed to more fully study AD-implicated proteins simply do not exist. Chemical probes enable functional modulation of systems at all levels of study—cell, organoid, tissue, animal and human—and are the basis of drug development efforts; thus, it is imperative that we develop a chemical probe development strategy that can keep pace with the rate of vulnerable gene/protein elucidation. Here, we propose development and testing of a platform technology that could be generalized to identify hits and develop chemical probes for GWAS-implicated proteins. We focus our initial effort on MS4A protein, the function of which is not fully elucidated, and yet which appears to influence the risk of developing AD, and is the subject of other protocol and technology development within the CureAlz Neuroinflammation Consortium. Through the development of this discovery platform, we will provide MS4A modulators (e.g., antagonists and agonists) that facilitate the study of the receptor system, and also provide hits for drug development.


Funding to Date

$200,000

Focus

Drug Discovery, Immune System Structures

Researchers

Jacob Hooker, Ph.D.