Molecular Mechanisms Underlying Somatotrope Differentiation and Function

生长素分化和功能的分子机制

• 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
• 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

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.

GH缺乏症（GHD）可能是由人数不足引起的，或者是体育体的无法 产生足够数量的GH，导致儿童身材矮小，心血管均大量和 由于代谢功能障碍而导致的成人脑血管死亡率。 GH替换的当前方法无法 概括正常的GH分泌模式，价格昂贵，并且在减少心血管方面的成功有限 疾病。众所周知的是，同源域转录因子POU1F1是必需的 未分化的祖细胞的祖细胞，甲状腺和乳糖谱系。但是，每个 这些单独的单元类型尚不清楚。该提案中概述的研究旨在解决 分子机制在体育型分化以及最终功能。基本的螺旋环 - 螺旋转录因子NeuroD4是种子分化和产后生长所必需的。 不幸的是，尚未研究NeuroD4作用的机制。新颖的初步数据显示 FOXO1调节动物和细胞模型中的NeuroD4表达并结合推定的增强子 与NeuroD4相关。拟议研究的长期目标是了解垂体 为了告知垂体疾病的治疗疗法，器官发生和功能。目的 该建议是确定FOXO1和NeuroD4调控的分子机制 躯体成熟和功能。中心假设是FoxO1和Neurod4是关键大师 体育体分化和功能的调节剂。该提议的理由是有关键 需要了解种子体分化和功能的分子机制，以便 改善GHD和代谢功能障碍的疗法。在没有这些信息的情况下，这些疗法将 继续在降低患者的发病率和死亡率方面取得有限的成功。中心假设将是 通过追求两个具体目的测试：1）调查FOXO1调节的机制 NeuroD4表达并确定该调节对体型分化和 功能和2）研究型神经4调节的机制的体长分化 和功能。拟议的研究具有创新性，因为它们将开发新颖的细胞和小鼠模型 并采用尖端技术。拟议的研究很重要，因为它将确定 管理躯体分化和功能的分子机制将有所改善 用于GHD和代谢功能障碍患者的治疗剂。预期的结果是1）进步 对调节种子分化和功能的因素的理解，2） 设计组织特异性小鼠模型，3）扩大分子诊断并改善了治疗疗法 GHD和代谢功能障碍。结果将产生重要的积极影响，因为它们将减少 通过告知改善GHD和代谢功能障碍的治疗方法，患者的发病率和死亡率。