Om Khuperkar
Pronouns: he/him
Research Mentor(s): Ken Inoki
Research Mentor School/College/Department: LSI/MIP / Medicine
Program:
Authors: Om Khuperkar, Ken Inoki, Shota Yoshida
Session: Session 5: 2:40 pm – 3:30 pm
Poster: 14
Abstract
Understanding the intricate mechanisms by which the mechanistic target of rapamycin (mTOR) signaling pathway operates is crucial for advancing medical research given that dysregulation of mTOR signaling is implicated in a myriad of human health problems, including cancer, metabolic disorders, neurodegenerative diseases, and aging. mTOR is an evolutionarily conserved serine/threonine kinase that governs essential cellular processes. My research focuses on revealing the molecular mechanisms by which mTORC1 activity is regulated by various nutrients and FDA-approved drugs, such as metformin, that are known to inhibit mTORC1 activity through undefined mechanisms. mTORC1 is known to be recruited to the lysosomal membrane for its activation. Interestingly, nutrients, including amino acids, glucose, and cholesterol, are known to enhance lysosomal mTORC1 localization, a process critical for mTORC1 activation. In contrast, metformin has been proposed to inhibit lysosomal v-ATPase activity, thereby attenuating lysosomal mTORC1 localization. However, the precise molecular mechanisms underlying the spatial regulations of lysosomal mTORC1 by glucose metabolites, certain lipids (e.g., phospholipids), and metformin remain elusive. Utilizing advanced techniques such as immuno-purification of lysosomes and quantitative mass spectrometry analyses in cell culture and tissues, we will determine alterations of lysosome-associated proteins in the presence or absence of these mTORC1 regulators. The proteins with lysosomal expression that are largely affected by these treatments (e.g., glucose starvation and metformin treatment) will be further investigated to determine if these proteins act upstream or downstream of mTORC1 activity in the cell culture system by generating knockdown or knockout cell lines. Our ultimate goal is to uncover novel regulations of nutrient- and drug-sensing mechanisms that regulate mTORC1 and explore their far-reaching implications in diseases such as obesity, diabetes, and cancer.
