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Molecular Mechanisms Underlying Somatotrope Differentiation and Function

生长素分化和功能的分子机制

基本信息

批准号：
10359404
负责人：
Buffy Sue Ellsworth
金额：
$ 44.25万
依托单位：
SOUTHERN ILLINOIS UNIVERSITY CARBONDALE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10359404
关键词：
Address Adult Animal Model BHLH Protein Binding Binding Sites CRISPR/Cas technology Cardiovascular Diseases Cardiovascular system Cell Line Cell model Cells Child Chromatin Consensus Consensus Sequence Data Development Enhancers Exhibits FOXO1A gene Failure Gene Expression Genes Genetic Recombination Genetic Transcription Goals Growth Hormone secretion Hypopituitarism Impairment Individual Introns Knowledge Lactotrope Cell Lead Life Literature Measures Mediating Metabolic dysfunction Metabolism Methods Mission Molecular Molecular Diagnosis Morbidity - disease rate Mus Mutation Organogenesis Outcome Patients Pattern Pituitary Diseases Pituitary Gland Pituitary Hormones Process Public Health Recombinant Growth Hormone Regulation Reporter Research Research Personnel Role Somatotrope Cell Somatotropin Specific qualifier value Techniques Testing Therapeutic Tissues Training Transgenic Organisms Undifferentiated United States National Institutes of Health cell type cerebrovascular design experience forkhead protein graduate student growth hormone deficiency homeodomain hormone deficiency improved innovation insight mortality mouse model novel novel diagnostics novel therapeutic intervention pituitary gland development postnatal progenitor response success tool transcription factor transcriptome sequencing undergraduate student

项目摘要

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.

生长激素缺乏症（GHD）可由生长激素数量不足或生长激素缺乏引起