Thursday, April 3, 2025
4/3/2025
Molecular Mechanisms Underlying Somatotrope Differentiation and Function - 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 will have an important positive impact because they will reduce patient morbidity and mortality by informing toward improved therapies for GHD and metabolic dysfunction.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).