Lucia Rameh-Plant, PhD - Principal Investigator and Research Associate Professor
Inositide crosstalk in mTor signaling and glucose metabolism.
Hometown - São Paulo, Brazil
B.S. Biological Sciences ........................ Universidade de São Paulo, Brazil
Ph.D. Biochemistry ................................... Universidade de São Paulo, Brazil
Principal Scientist Signal Transduction ........................ Boston Biomedical Research Institute
Res Asst Prof Medicine .......................................... Boston University School of Medicine
Res Assc Prof Biochemistry .................................... Vanderbilt University (John York)
Res Assc Prof Medicine and Biochemistry ............. Vanderbilt University Medical Center
Vanderbilt Diabetes Research Center (Al Powers)
See Lucia's Publications on PubMed
Signaling through the nutrient-sensing kinase mTORC1 (mechanistic Target of Rapamycin Complex 1) is directly linked to aging and age-associated diseases in mice, flies and worms. Nutrient overload is a well-known aging factor that stimulates mTORC1 hyperactivation in many tissues, whereas dietary restriction downregulates mTORC1 activity to promote longevity. Remarkably, mTORC1 inhibition through rapamycin treatment is the only pharmacological intervention that extends the lifespan of all animal models of accelerated aging. Unfortunately, the use of rapamycin to treat patients is limited by metabolic and immunological off- target effects. Thus, fresh perspectives on how to modulate mTORC1 signaling are needed.
Recent structural studies revealed that a small molecule metabolite called inositol hexakisphosphate (IP6) forms a stable complex with mTOR, the catalytic subunit of mTORC1 and mTORC2, and that mutations in the mTOR residues that coordinate IP6 reduced mTOR kinase activity in vitro. Building on these observations, we generated data strongly suggesting that IP6 promotes the formation of a denaturation-resistant high molecular weight complex containing mTOR and RAPTOR, the regulatory subunit of mTORC1. How IP6 binding to mTOR regulates mTORC1 assembly and signaling in vivo is unknown. Interestingly, single nucleotide polymorphisms in IPMK, an enzyme responsible for IP6 production, was recently associated with longevity in women and lower risk for Late Onset Alzheimer Disease. Yet, the impact of IP6 metabolism on premature aging has not been experimentally addressed.
The overarching goal of my current work is to unveil the molecular mechanisms by which IP6 regulates mTORC1 signaling and to assess how IP6 metabolism contributes to premature aging. Our working hypotheses is that IP6 stabilizes the mTOR/RAPTOR association to promote hyperactivation of the complex, an event that if perturbed will protect against nutrient- induced premature aging.
In close collaboration with members of the Blind Lab, our team is now determining the impact of inositol phosphates on mTOR physiology and cellular aging. We recently reported that excess glucose stimulates mTORC1 signaling through unconventional mechanisms. Glucose metabolism can directly and indirectly affect IP6 levels in cells. We are now examining how suppression of enzymes in IP6 synthesis affects mTORC1 signaling and cellular aging. Using a mutant mTOR that is unable to bind IP6, we are also assessing whether IP6 is necessary for mTORC1/2 complex formation, stability or activation in the context of glucose overload.
Further, in collaboration with Kris Burkewitz here at Vanderbilt, we are also conducting studies to determine how inositol phosphate metabolism regulates longevity. The role of mTORC1 suppression in the extension of lifespan by dietary restriction has been well documented in C. elegans, a classic model for studying the genetics of aging. In contrast, it is not known whether inositol phosphate metabolism affects the lifespan of worms or other organisms. We are now suppressing IPMK and IPK1 in C. elegans and assessing whether targeting IP6 metabolism can extend lifespan. Epistasis studies are also being performed to establish how mTORC1 and IPMK/IPK1 pathways interact to regulate longevity in worms.
Thus, work in our group explores a novel mechanism for the regulation of mTOR activity in vivo and a new role for inositol phosphates in nutrient-induced premature aging. Future work will pursue the mechanisms by which inositol phosphate species impact metabolism and aging from a functional aspect and validate the enzymes in the inositol pathways as potential targets for preventing premature aging in various organisms.