Hughes, Michael P. (2013 - 2016)
Michael is in the Department of Biological Chemistry. He joined the training program in 2013. His research mentor is Dr. David Eisenberg. He received a B.A. degree in 2012 from Colorado State U.
Mentor: Dr. David Eisenberg
Understanding amyloid proteins and their associated disorders has challenged scientists for decades. All of these diseases remain uncurable, and present an ever increasing economic and societal drain. First and foremost in this respect is Alzheimer's disease (AD), now the sixth leading cause of death in the United States. Developing therapeutics has remained a difficult task for researchers due to the nature of amyloigenic proteins. Amyloigenic proteins are typically promiscuous in the space that they sample, and can organize into many structually distinct complexes. Amyloid Beta (Aβ) and tau, the commonly attributed etiological agents in AD, can form both soluble oligomeric species and insoluble fibrous aggregates. The dynamic and fluid nature of these proteins makes traditional structure based discovery of drugs difficult, but not impossible. The Eisenberg lab has characterized the fibrous spines, termed a “steric zipper”, found in Aβ and tau as well as a dozen other amyloid diseases. A steric zipper is comprised of a series of beta-strands (either parallel or anti-parallel) stacking along the fiber axis to form a continuous beta-sheet and two such sheets mate with their residue side chains interdigitating. With structural data available, a methodology involving computational screening, confirmation of binding, and toxicity assays was developed to search for and characterize small molecules, known as Binders of Amyloid Fibrils (BAFs), in an attempt to find compounds capable of reducing toxicity of amyloid proteins. This procedure was used to find BAFs for Aβ, but has yet to be rigorously applied to tau. Building upon these discoveries, I am interested in using structural knowledge of the steric zippers of tau to screen for and refine BAFs to reduce the cytotoxicity tau in physiologically relevant models.
