# Investigating structure-function relationships of disease variants encoded by the diabetes gene Clec16a

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $42,636

## Abstract

Abstract
 This F31 proposal describes a comprehensive training and mentorship program for Morgan Gingerich, a
Ph.D. candidate in the Cellular and Molecular Biology program at the University of Michigan. Ms. Gingerich will
participate in a rigorous didactic and laboratory training curriculum, supervised by her co-mentors, Drs.
Soleimanpour and Schnell, as well as support from a multi-disciplinary mentorship/thesis committee. Her training
program will include supervised molecular, structural, and biophysical training from a team of scientific experts,
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. Gingerich for an independent and productive scientific career.
 Diabetes is a global epidemic of increasing prevalence. All forms of diabetes stem from insufficient beta-
cell function and/or mass to meet peripheral insulin demands. Mitochondrial bioenergetics are critical for beta-
cell function, and are disrupted in all forms of diabetes. The long-term objective of my project is to clarify
genetic, molecular, and structural mechanisms contributing to beta cell mitochondrial dysfunction in diabetes.
Our lab has identified the T1D gene CLEC16A to encode an E3 ligase that regulates selective elimination of
damaged/dysfunctional mitochondria via mitophagy. Despite our identification of Clec16a as an E3 ligase, there
is no available information identifying conserved functional or structural domains. The overall goal of this project
is to define structure-function relationships in Clec16a, through the study of a novel human Clec16a disease-
associated isoform which lacks internal/C-terminal regions. Our preliminary data indicate that loss of the Clec16a
C-terminus leads to glucose intolerance and beta cell mitochondrial function in vivo, and that both the internal
and C-terminal domains affect Clec16a stability and assembly within a key mitophagy regulatory complex. I
hypothesize that the Clec16a disease-variant lacks structural and functional regions critical for the maintenance
of beta-cell mitophagy and insulin secretion. I will test this hypothesis in the following Specific Aims:
 Aim 1 will elucidate the role of the Clec16a disease variant in regulating beta-cell function and mitophagy
using primary islets from a novel Clec16a C-terminal knockout mouse. I will also assess beta-cell function and
mitophagy by re-expressing internal/C-terminal mutants and the disease variant in a Clec16a null beta-cell line.
 Aim 2 will determine the structural properties and molecular functions of the Clec16a internal and C-
terminal regions, clarifying their biological role in disease susceptibility. We will use NMR and informatics to
assess Clec16a structure. We will determine the mechanism by which regions lost in the Clec16a disease-
associated variant alter Clec16a levels/stability and mitophagy complex assembly using mutagenesis and
biochemical assays...

## Key facts

- **NIH application ID:** 10112102
- **Project number:** 5F31DK122761-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Morgan Gingerich
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $42,636
- **Award type:** 5
- **Project period:** 2020-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10112102

## Citation

> US National Institutes of Health, RePORTER application 10112102, Investigating structure-function relationships of disease variants encoded by the diabetes gene Clec16a (5F31DK122761-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10112102. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*