The laboratory’s long term research goal is to develop a comprehensive understanding of Proteostasis and how alterations in this process contribute to normal biological and disease processes. Although much is known about the role of transcriptional and translational control of gene expression in various human disorders, the extent to which protein degradation contributes to disease processes remains vastly unexplored.
Key to understanding protein degradation is to elucidate the mechanisms by which the 26S proteasome is regulated in vivo. While it is known that regulation of proteasome activity is intrinsically linked to its local availability and protein-protein interaction profile, detailed mechanistic insights are still lacking. Further complicating things, we know virtually nothing of the intimate relationship that must exist between protein synthesis and degradation to regulate protein homeostasis, and the effects of environmental stresses on these processes. For example, dietary restriction, aging and environmental stresses have all been linked to proteasome deregulation through an unknown mechanism. Therefore, knowledge gained from our future endeavors will not only advance the basic understanding of protein homeostasis in the broader context of biology, but will also open up new therapeutic opportunities against those diseases that arise secondary to accumulation of misfolded “toxic” proteins such as cancer, amyotrophic lateral sclerosis (ALS), Retinitis Pigmentosa, and Alzheimer’s and Parkinson’s diseases. As a first step towards this goal, we will take advantage of the laboratory’s unique set of skills in clinical medicine, biochemistry, cell & molecular biology, and Drosophila and Mouse genetics, to further extend these lines of work using a multi-pronged interdisciplinary approach.