Monday, April 29, 2024
4/29/2024
Abstract This F31 proposal describes a comprehensive training and mentorship program for Belle Henry, a Ph.D. candidate in the Immunology program at the University of Michigan. Ms. Henry will participate in a rigorous didactic and laboratory training curriculum, supervised by her mentor as well as support from a multi-disciplinary mentorship and dissertation committee. Her training program will include supervised molecular, structural, and biochemical training, as well as mentored opportunities to engage in scientific writing, presentations, and grant applications. The ultimate goal of this proposal is to best position Ms. Henry for an independent and productive scientific career. Diabetes is a global epidemic of increasing prevalence, where all forms of diabetes are linked by insufficient ß-cell function or mass to meet peripheral insulin demands. Type 1 diabetes (T1D) is caused by a combination of both intrinsic ß cell dysfunction and dysregulation of the immune system, thus leading to autoimmune attack and ß cell demise. As ß cells are uniquely sensitive to inflammatory damage, therapies targeting the ß cell present opportunities for treatment of T1D. The long-term objective of my project is to better understand the molecular mechanisms that govern ß-cell responses to inflammatory challenge and gain greater insight into the mechanisms that regulate ß cell survival. My project focuses on the ß-cell-specific role of leucine-rich repeat kinase 2 (LRRK2), a kinase that phosphorylates Rab GTPases to regulate membrane trafficking. My preliminary data indicate that LRRK2 is transcriptionally induced in ß cells following cytokine exposure, and pharmacologic inhibition of LRRK2 protects ß cells against pro-inflammatory cytokine-induced death. The overall objective of my project is to understand the role of LRRK2 in ß-cell responses to inflammatory toxicity. LRRK2 has been shown to regulate mitophagy in other cell types, and previous work from the Soleimanpour lab demonstrates that ß cells regulate mitochondrial turnover to promote cell survival in pro- inflammatory contexts. Thus, I hypothesize that in response to inflammatory damage, LRRK2 modulates ß cell survival through regulation of mitophagy, which I will test through 2 Specific Aims. Aim 1 will determine the importance of LRRK2 to ß cell function and survival in mouse models of ß cell inflammation and primary human islets. Aim 2 will elucidate the mechanistic impact of LRRK2 induction on mitochondrial quality control following inflammatory damage by examining its role in mitophagy. Successful completion of these Aims will provide novel and critical insights into the mechanistic responses of ß cells to inflammatory stimuli that could be targeted to defend ß-cells to treat or prevent diabetes.
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).
