Roles of STAT5b in IGF-I Production and Human Growth

STAT5b 在 IGF-I 产生和人类生长中的作用

• 批准号: 8757797
• 负责人: Vivian Hwa
• 金额: $ 32.37万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8757797
• 关键词: Address; Affect; Area; Child; Clinical; Clinical Endocrinology; Clinical Immunology; Collection; Cytokine Signaling; Defect; Dermal; Diagnosis; Drops; Exhibits; Failure; Fibroblasts; Genes; Growth; Growth Hormone Receptor; Growth and Development function; Height; Human; Human Development; IGF1 gene; Immune; Inflammatory; Insulin-Like Growth Factor I; Interferons; Knock-out; Life; Mediating; Molecular; Mus; Mutation; Nuclear; Observational Study; Pathogenesis; Pathway interactions; Patients; Phase; Positioning Attribute; Production; Property; Proteins; Receptor Signaling; Recording of previous events; Recruitment Activity; Regulation; Residual state; Role; STAT1 gene; STAT5b Transcription Factor; Sequence Analysis; Signal Pathway; Signal Transduction; Somatomedins; Somatotropin; Specificity; Structure; Syndrome; System; Therapeutic; Time; Tyrosine; Variant; base; cytokine; exome sequencing; falls; hormone regulation; human GHR protein; immune function; improved; in vivo; mouse model; postnatal; public health relevance; src Homology Region 2 Domain

DESCRIPTION (provided by applicant): The insulin-like growth factor (IGF)-I system is critical for all phases of human development, growth, and maturation. While it is well established that IGF-1 production is highly dependent on growth hormone (GH) during postnatal life, mechanisms of regulation are still poorly understood, as reflected by the 1-2% children who drop below the normal growth curves, many of whom respond poorly to GH (including therapeutic GH) and are IGF-1 deficient. GH regulates the production of IGF-1 primarily through activation of the GH receptor (GHR) signaling cascades. The identification of rare mutations of STAT5B (signal transducer and activator of transcription 5B) in children who resembled patients carrying GHR defects, with severe postnatal growth failure, GH insensitivity (GHI) and severe IGF deficiency (IGFD), confirmed the critical importance of STAT5b, over that of the STAT1, 3 and 5a signaling pathways, in IGF-1 production and human growth. Patients with STAT5b deficiency, moreover, also presented with histories of immune dysregulation, indicating the importance of STAT5b in many cytokine systems. These clinical presentations of a STAT5b deficiency state are unique to humans. Of note, the presence of the closely related STAT5a (which shares >90% similarity with STAT5b at the protein level) could not compensate for human loss of STAT5b functions, thereby providing the first compelling in vivo evidence for human STAT5b and STAT5a as having distinct and non-redundant functions despite their high degree of identity. The hypothesis of this proposal, based on clinical observations, is that GH regulation of IGF-1 production in humans is mediated predominantly, if not exclusively, through STAT5b. This proposal will address how STAT5b transduces GH signals to regulate IGF-1 production by investigating molecular mechanisms of STAT5b actions, from structure/function to cell signaling, and their relationship to clinical endocrinology and immunology, using identified mutations as human functional knockouts. The Specific Aims will (1) decipher the specificity of human GHR-STAT5b structural interactions, the critical first step in regulating IGF-1 production; (2) delineate STAT5b properties necessary for IGF-1 production from those necessary for immune functions; (3) determine whether cross talk with other cytokine signaling pathways modulate STAT5b- dependent activation IGF-1 production. Humanized mouse model can then be generated to recapitulate the human STAT5b deficiency condition. Exome sequence analysis of unresolved clinical cases of severe IGFD with immune deficiencies has revealed potential new mechanisms of modulating STAT5b actions. At the conclusion of these studies, this proposal will have identified and confirmed the mechanism(s) for specificity of GHR-STAT5b interactions, identified new mechanism(s) for modulating STAT5b activation and regulation of IGF-1 production, and identified new targets for analyzing GHI and IGFD syndromes. In the long term, these results will provide the basis for improved diagnosis and therapy management of affected children.

描述（由申请人提供）：胰岛素样生长因子(IGF)- 1系统对人类发育、生长和成熟的所有阶段都至关重要。虽然已经确定IGF-1的产生高度依赖于出生后生活中的生长激素（GH），但其调节机制仍然知之甚少，这反映在1-2%的儿童低于正常生长曲线，其中许多儿童对GH（包括治疗性GH）反应不佳，并且缺乏IGF-1。生长激素主要通过激活生长激素受体（GHR）信号级联来调节IGF-1的产生。在与携带GHR缺陷、严重出生后生长衰竭、GH不敏感（GHI）和严重IGF缺乏（IGFD）的患者相似的儿童中，发现了罕见的STAT5B（信号换能器和转录激活因子5B）突变，证实了STAT5B在IGF-1产生和人类生长中比STAT1、3和5a信号通路更为重要。此外，STAT5b缺乏的患者还表现出免疫失调的历史，这表明STAT5b在许多细胞因子系统中的重要性。这些STAT5b缺乏状态的临床表现是人类独有的。值得注意的是，与STAT5a密切相关的STAT5a（在蛋白水平上与STAT5b有90%的相似性）的存在并不能弥补人类STAT5b功能的缺失，从而首次提供了令人信服的体内证据，证明人类STAT5b和STAT5a尽管高度同源，但具有不同的非冗余功能。基于临床观察，这一提议的假设是，生长激素对人类IGF-1产生的调节主要是通过STAT5b介导的，如果不是唯一的话。该提案将通过研究STAT5b作用的分子机制，从结构/功能到细胞信号，以及它们与临床内分泌学和免疫学的关系，研究STAT5b如何转导GH信号来调节IGF-1的产生，使用已识别的突变作为人类功能敲除。具体目标将(1)破译人类GHR-STAT5b结构相互作用的特异性，这是调节IGF-1产生的关键第一步；(2)区分IGF-1产生所需的STAT5b特性和免疫功能所需的STAT5b特性；(3)确定与其他细胞因子信号通路的串扰是否调节STAT5b依赖性激活IGF-1的产生。然后可以生成人源化小鼠模型来重现人STAT5b缺失情况。对未解决的伴有免疫缺陷的严重IGFD临床病例的外显子组序列分析揭示了调节STAT5b作用的潜在新机制。在这些研究的结论中，本提案将确定并确认GHR-STAT5b相互作用特异性的机制，确定调节STAT5b激活和调节IGF-1产生的新机制，并确定分析GHI和IGFD综合征的新靶点。从长远来看，这些结果将为改善受影响儿童的诊断和治疗管理提供基础。