I am an early career physician-scientist working to build a molecular understanding of the human LINE-1 transposon (L1) and leverage transposon biology into novel strategies for early diagnosis, prevention, and treatment of cancer and other diseases of aging. My thesis work in Pharmacology at Johns Hopkins with Phil Cole and Jef Boeke clarified the role of the gut hormone ghrelin as a fat sensor modulating metabolism, rather than “hunger hormone” and developed a proof-of-concept ghrelin octanyltransferase (GOAT) inhibitor that afforded glucose and weight control in mice. My studies in the Boeke lab on L1 before returning to medical school identified key host interactions in the L1 lifecycle and developed novel systems and reagents to study L1 that are now in wide use and enable my current work and this proposal. Postdoctoral training in Sabatini, Cole, and Burns research groups provided world-class scientific environments with extensive experience in biochemistry, cell and signaling biology, structural biology, and cancer biology. My clinical training in gastrointestinal pathology complements my scientific background, providing a unique perspective on pathophysiology and opportunities to translate bench discoveries to bedside. I have successfully made contributions to understanding disease mechanisms and developed diagnostics and therapeutic strategies that I believe illustrate my future potential. This includes discovering a novel serious adverse pulmonary reaction to the common antibiotic Bactrim, the broad utility of L1 tools we have developed, and novel tissue and plasma assays for L1 that show promise in early cancer diagnosis, therapeutic monitoring, and prognostics. Bolstered heavily by knowledge gained in my postdoctoral training on the study of mTORC2-Akt and the discovery of the mechanism of Akt recognition, I am now focused on elucidating the functions of L1, where I now have >10 years’ experience. My recent work revealed the first structures of the key L1 ORF2 reverse transcriptase (RT), provides key mechanistic insights into L1 polymerization and insertion, discovered cytosolic RT activity that provides a mechanistic explanation for contributions of L1 to sterile inflammation (“viral mimicry”), and will enable rational drug development. In my lab at Brown University in the Center on the Biology of Aging and Legorreta Cancer Center, we are dissecting LINE mechanism and pathophysiology, building a detailed molecular understanding of L1:host interactions and their consequences, and leveraging these insights into novel diagnostics and therapeutics.
