The role of LRRK2 in pancreatic beta cell responses to inflammatory damage

Ended Project Grant Awarded Last action

Award ID
F31DK138544
Recipient
Awarding agency
Obligated
$174,368

Award facts

Completion date
Place of performance
Michigan, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

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.

Transactions

Action Obligated Date
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Amendment $1,780
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Amendment $42,702
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Quick answers

Who received award F31DK138544?

F31DK138544 was awarded to Regents Of The University Of Michigan by National Institute of Diabetes and Digestive and Kidney Diseases (National Institutes of Health) on September 18, 2024.

How much is award F31DK138544 worth?

$174,368 has been obligated on F31DK138544.

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