# Jagged 1-Notch signaling determines β cell maturity and function

> **NIH NIH F32** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $74,886

## Abstract

Summary/Abstract
 Obesity-induced Type 2 Diabetes (T2DM) continues to increase at an alarming rate resulting in a substantial
burden of long-term complications and healthcare costs. T2DM is now the leading cause of end-stage renal disease
and one of the leading causes of blindness worldwide, as well as a disproportionate contributor to cardiovascular
morbidity and mortality. As such, understanding mechanisms of T2DM pathogenesis is key in tackling the growing
prevalence in what some consider the largest epidemic in human history.
 Although insulin resistance is the hallmark of Type 2 diabetes (T2DM), it manifests as hyperglycemia only in
the setting of β cell insufficiency. Pathophysiologic mechanisms underlying this failure requires further elucidation.
We have recently shown that Notch signaling is a novel regulator of β cell function, and glucose homeostasis. Notch
activity is regulated by ligand (Jagged 1/2, and Delta-like 1/3/4) availability. We find that islets isolated from HFD-fed
or leptin receptor-deficient db/db mice have increased Jagged1 expression as compared to chow or db/+ controls,
without change in other Notch ligands, in parallel to increased Notch activity. These data led us to hypothesize that
Jagged1 is both sufficient and necessary to transduce Notch signaling in β cells and is a potential regulator of β cell
function, maturity and glucose homeostasis (Aim 1 and Aim 2). To investigate this, we generated novel β cell specific
Jagged1 gain-of-function and knock-out mice. By identifying the ligand-receptor interaction, we postulate that we can
take advantage of this knowledge for therapeutic benefit. To this end, we have generated dominant negative mutants
of the Notch receptor lacking the intracellular Notch domain that specifically block either Jagged or Delta-like ligands.
As a translational approach, we will investigate if increased Jagged1 is also seen in islets from patients with and without
T2DM (Aim 3). The current data on Notch signaling in β cells shows promise for furthering the understanding of the
pathophysiology in T2DM. In studying this mechanism further, we hope to provide a novel therapeutic strategy in
preventing a disease that continues to be a growing concern worldwide.
 This training plan will develop my skills in understanding determinants of β cell function and maturity in the
setting of hyperglycemia. The proposed study investigating Jagged 1-Notch signaling will be a stepping stone towards
my goal of becoming an independent researcher.

## Key facts

- **NIH application ID:** 10315442
- **Project number:** 1F32DK127862-01A1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Nina Suda
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $74,886
- **Award type:** 1
- **Project period:** 2021-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10315442

## Citation

> US National Institutes of Health, RePORTER application 10315442, Jagged 1-Notch signaling determines β cell maturity and function (1F32DK127862-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10315442. Licensed CC0.

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