# Molecular Mechanisms Underlying Somatotrope Differentiation and Function

> **NIH NIH R15** · SOUTHERN ILLINOIS UNIVERSITY CARBONDALE · 2022 · $442,500

## Abstract

GH deficiency (GHD) can be caused by inadequate numbers of somatotropes or the inability of somatotropes
to produce sufficient amounts of GH, resulting in short stature in children and significant cardiovascular and
cerebrovascular mortality in adults due to metabolic dysfunction. Current methods of GH replacement fail to
recapitulate normal GH secretion patterns, are expensive, and have limited success in reducing cardiovascular
disease. It is well-established that the homeodomain transcription factor, POU1F1, is required for commitment
of undifferentiated progenitors to the somatotrope, thyrotrope, and lactotrope lineages. However, how each of
these individual cell types is specified is not clear. The studies outlined in this proposal aim to address the
molecular mechanisms underlying somatotrope differentiation and, ultimately, function. The basic helix-loop-
helix transcription factor, NEUROD4, is required for somatotrope differentiation and postnatal growth.
Unfortunately, the mechanism of NEUROD4 action have not been investigated. Novel preliminary data show
that FOXO1 regulates Neurod4 expression in animal and cell models and binds a putative enhancer
associated with Neurod4. The long-term goal of the proposed studies is to understand pituitary
organogenesis and function in order to inform improved therapeutics for pituitary diseases. The objective of
this proposal is to determine the molecular mechanisms underlying FOXO1 and NEUROD4 regulation of
somatotrope maturation and function. The central hypothesis is that FOXO1 and NEUROD4 are key master
regulators of somatotrope differentiation and function. The rationale for this proposal is that there is a critical
need to understand the molecular mechanisms underlying somatotrope differentiation and function in order to
improve therapies for GHD and metabolic dysfunction. In the absence of this information, these therapies will
continue to have limited success in reducing patient morbidity and mortality. The central hypothesis will be
tested by pursuing two specific aims: 1) Investigate the mechanisms underlying FOXO1 regulation of
Neurod4 expression and determine the contribution of this regulation to somatotrope differentiation and
function, and 2) Investigate the mechanisms underlying NEUROD4 regulation of somatotrope differentiation
and function. The proposed studies are innovative because they will develop novel cell and mouse models
and employs cutting edge techniques. The proposed research is significant because it will identify the
molecular mechanisms governing somatotrope differentiation and function that will inform for improved
therapeutics for patients with GHD and metabolic dysfunction. The expected outcomes are 1) advances in
the understanding of factors that regulate somatotrope differentiation and function, 2) potential tools for
designing tissue-specific mouse models, and 3) expanded molecular diagnoses and improved therapeutics for
GHD and metabolic dysfunction. The results ...

## Key facts

- **NIH application ID:** 10359404
- **Project number:** 1R15HD107430-01
- **Recipient organization:** SOUTHERN ILLINOIS UNIVERSITY CARBONDALE
- **Principal Investigator:** Buffy Sue Ellsworth
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $442,500
- **Award type:** 1
- **Project period:** 2022-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10359404

## Citation

> US National Institutes of Health, RePORTER application 10359404, Molecular Mechanisms Underlying Somatotrope Differentiation and Function (1R15HD107430-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10359404. Licensed CC0.

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