# Mechanisms mediating human enteroendocrine cell differentiation and function

> **NIH NIH K08** · BOSTON CHILDREN'S HOSPITAL · 2024 · $167,940

## Abstract

PROJECT SUMMARY
The twin epidemics of obesity and type 2 diabetes mellitus (T2DM) continue to worsen, highlighting a growing
need to understand the dysregulation of appetite and insulin secretion that contribute to these diseases.
Enteroendocrine cells (EECs) are key regulators of both appetite and insulin secretion. Thus, the long-term
goal of this project is to understand the transcriptional and epigenetic regulation of EEC differentiation and
function, and how this is perturbed in disease states. The overall objective of this application is to identify and
evaluate factors that are necessary for EE differentiation and hormone production/secretion. The central
hypothesis is that EEC growth and function are controlled by intrinsic and extrinsic factors. Intrinsically, we
have shown that FOXO1 inhibition (AS) and, separately, CB1/JNK inhibition (RSP) induce human EE
differentiation, but the mechanisms driving this are not known. Extrinsically, nutrients are known to regulate EE
hormone production, but it is unclear how other factors, including disease-related cytokines and hormones,
alter this response. The rationale for this proposal is that through a better understanding of EEC differentiation
and function, unique therapies can be developed to regulate appetite and insulin secretion via EE hormones.
The central hypothesis will be evaluated in two specific aims: 1) to identify the role of HES6 and LMX1B in
human EE differentiation and to identify the epigenetic and transcriptional changes driven by AS and RSP
during early EE differentiation; and 2) to evaluate the impact of cytokines and hormones on nutrient-stimulated
EEC function. In Aim 1, we will study gene expression changes (using CRISPR/Cas9, SHARE-seq), epigenetic
changes (using SHARE-seq, bulk ATAC-seq), and protein interactions (using co-immunoprecipitation) in
human duodenal organoids to investigate the roles of HES6 and LMX1B and to identify new factors involved in
early stages of EE differentiation. In Aim 2, we will assess the ability of EECs (derived from duodenal and
rectal organoids) to recapitulate the response of native EECs to nutrient stimulation. We will assess hormone
production and secretion (using ELISA, qPCR), and how these responses are dysregulated following exposure
to obesity/T2DM-associated cytokines and hormones. The candidate for this K08 proposal is Daniel Zeve, MD,
PhD, a pediatric endocrinologist with expertise in developmental biology and metabolism. With his mentor, Dr.
David Breault, Dr. Zeve has designed a career development plan to achieve scientific independence. This plan
will be performed at Boston Children’s Hospital, allowing the applicant access to a multitude of resources
throughout the Harvard Medical system. During the award period, the applicant will gain additional experience
in SHARE-seq, epigenetics, CRISPR/Cas9, and bioinformatics through multiple avenues, including
coursework, seminars, and high-level collaborations. This innovative project...

## Key facts

- **NIH application ID:** 10890848
- **Project number:** 5K08DK134885-02
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Daniel Richard Zeve
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $167,940
- **Award type:** 5
- **Project period:** 2023-08-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10890848

## Citation

> US National Institutes of Health, RePORTER application 10890848, Mechanisms mediating human enteroendocrine cell differentiation and function (5K08DK134885-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10890848. Licensed CC0.

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