Friday, November 22, 2024
11/22/2024
Project Summary The goal of this K08 application is to provide a rigorous 5-year scientific and careered development training plan that will facilitate Dr. Josephine Thinwa to transition from a post-doctoral fellow to an independent investigator. The candidate completed her MD/PhD degree at UT Health San Antonio where she focused on innate immunity. After completing internal medicine and infectious diseases training at UT Southwestern, she joined the lab of Dr. Beth Levine, a renowned expert in autophagy, to pursue a project on the interface between autophagy and antiviral immunity. Autophagy is known to function in antiviral innate immunity by specifically targeting intracellular viral components for lysosomal degradation, a process called virophagy. However, how virophagy is activated and regulated is still poorly understood. Based on an unbiased screen for host genes necessary for autophagy induction during infection with two prototypic neurotropic viruses, Sindbis virus (SINV) and Herpes Simplex Virus-1 (HSV-1), her preliminary work identified CDKL5 as a candidate novel regulator of virophagy. She demonstrated that cells deficient in CDKL5 accumulated high levels of SINV capsid protein. Additionally, she determined that CDKL5KO mice were more susceptible to lethal CNS infections with SINV and HSV-1, suggesting that CDKL5 is a critical host antiviral factor. After learning of her mentor’s likely terminal illness, Dr. Thinwa worked with Dr. Levine to establish a mentoring team of accomplished scientists who would provide the expertise and training necessary for her to successfully elucidate the function of CDKL5 in antiviral immunity and become an independent investigator. Her mentorship transitioned smoothly after Dr. Levine passed away to Dr. Michael Shiloh, her primary co-mentor who is a physician scientist and expert in innate immunity and autophagy, and Dr. Julie Pfeiffer, a renowned scientist in viral pathogenesis. They have successfully trained numerous postdoctoral fellows to achieve scientific independence. This mentoring team is perfectly complemented for the proposed studies at the interface between autophagy and antiviral immunity by her outside co-mentor Dr. Hebert “Skip” Virgin. He is a physician scientist and an undisputed leader in the field of autophagy and innate antiviral immunity. He also has a very strong track record of mentoring postdoctoral trainees. A committee of advisors and collaborators consisting of three outstanding scientists will provide additional scientific expertise to enhance her technical skills and offer guidance in scientific and career matters. In her proposed research, the applicant will aim to 1) define the function of CDKL5 in virophagy, 2) delineate which step(s) of the SINV life cycle are modulated by CDKL5, and 3) determine the role of CDKL5 in host antiviral response in vivo. Overall, the proposed studies are likely to expand our understanding of how host cells mitigate the toxic overproduction of viral proteins during infection. Together with access to excellent institutional resources, and training from didactic courses on leadership, grantsmanship and technical skills, she is positioned to become a successful physician- scientist focused on antiviral innate immunity.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
