# Pdx1 transcriptional activity and beta-cell function are dynamically modulated bycoregulators in physiological and pathophysiological conditions associated with Type 2 diabetes

> **NIH NIH K01** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $162,409

## Abstract

Project Summary/Abstract
 Pancreatic β-cells within the islets of Langerhans are required for glucose-stimulated insulin secretion and
glucose homeostasis. Dysfunctional β-cell activity and identity results in diabetes mellitus (DM), a growing
disease affecting millions of Americans, thus creating an enormous fiscal and health burden. Strategies to
improve outcomes for the mounting number of diabetic patients requires understanding the complex programs
that coordinate a proper insulin release in response to changing blood glucose levels. Developing upon existing
knowledge of how islet enriched transcription factors (TFs) coordinate signals that influence gene regulatory
programs will allow us to understand how such programs are dramatically altered in islet β-cells of diabetes
patients. Pdx1, one of the most important TFs in the developing and postnatal β-cell, has been shown to recruit
a diverse set of coregulators which could potentially modulate its activity. This proposal is focused around how
Pdx1:coregulator interactions are influential to normal β-cell function and are altered in pathophysiological
conditions associated with Type 2 diabetes (T2DM).
 The Swi/Snf ATP-dependent chromatin remodeling complex was found to interact with and control a subset
of Pdx1 target genes in a glucose dependent manner in vitro. Preliminary studies demonstrate that conditional
removal of Swi/Snf activity from mature islet β-cells significantly impacts β-cell function and identity in vivo.
Moreover, our lab found that Pdx1:Swi/Snf interactions are compromised in human T2DM donor samples, which
suggests that, in general, Pdx1:coregulator interactions are sensitive to the diabetic milieu. This proposal will
test the overall hypothesis that β-cell activity is regulated by coregulators whose interactions with Pdx1 are
dynamically controlled by physiological and pathophysiological conditions. In Aim 1, the applicant will utilize
unbiased genome-wide RNA-Sequencing, targeted ChIP, ChIP-ReChIP and bioinformatics approaches to define
the genes and pathways regulated by Pdx1:Swi/Snf in mature β-cells using transgenic Swi/Snf knockout mice.
Moreover, the influence of Swi/Snf on human Pdx1 and β-cell action will be investigated. Aim 2 will evaluate the
influence other Pdx1-recruited coregulators have on human and mouse β-cell function. In Aim 3, the applicant
will test how metabolic stress associated with T2DM affects Pdx1:Swi/Snf complex formation using in vivo rodent
models of T2DM and human islets.
 With this K01 Career Developmental Award, the applicant will be able to continue to focus their time on the
Aims outlined in this proposal. A significant amount of career training and research data will be acquired while
at the Vanderbilt University, which is more than equipped with the intellectual knowledge of faculty and core
facilities to carry out all of the proposed studies. Moreover, the candidate will develop the tools and skills
necessary to answer many of the qu...

## Key facts

- **NIH application ID:** 9994982
- **Project number:** 5K01DK115633-04
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Jason M Spaeth
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $162,409
- **Award type:** 5
- **Project period:** 2018-09-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9994982

## Citation

> US National Institutes of Health, RePORTER application 9994982, Pdx1 transcriptional activity and beta-cell function are dynamically modulated bycoregulators in physiological and pathophysiological conditions associated with Type 2 diabetes (5K01DK115633-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9994982. Licensed CC0.

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