Roles of STAT5b in IGF-I Production and Human Growth

描述（由申请人提供）：胰岛素样生长因子（IGF）-I系统对人类发育、生长和成熟的所有阶段都至关重要。虽然它是公认的，IGF-1的生产是高度依赖于生长激素（GH）在出生后的生活，调节机制仍然知之甚少，反映了1-2%的儿童谁下降到正常生长曲线以下，其中许多人对GH反应不佳（包括治疗GH）和IGF-1缺乏。GH主要通过激活GH受体（GHR）信号级联来调节IGF-1的产生。在患有严重的出生后生长障碍、生长激素不敏感性（GHI）和严重的IGF缺乏症（IGFD）的儿童中，发现了STAT 5 B（信号转导和转录激活因子5 B）的罕见突变，证实了STAT 5 b在IGF-1产生和人类生长中的重要性，超过了STAT 1、3和5a信号通路。此外，STAT 5 b缺乏的患者也有免疫失调的病史，表明STAT 5 b在许多细胞因子系统中的重要性。STAT 5 b缺乏状态的这些临床表现是人类独有的。值得注意的是，密切相关的STAT 5a（其在蛋白质水平上与STAT 5 b具有>90%的相似性）的存在不能补偿人STAT 5 b功能的丧失，从而提供了人STAT 5 b和STAT 5a具有不同和非冗余功能的第一个令人信服的体内证据，尽管它们具有高度的同一性。 基于临床观察，该建议的假设是，GH对人类IGF-1产生的调节主要（如果不是唯一的话）通过STAT 5 b介导。该提案将通过研究STAT 5 b作用的分子机制，从结构/功能到细胞信号传导，以及它们与临床内分泌学和免疫学的关系，使用鉴定的突变作为人类功能敲除，来解决STAT 5 b如何转导GH信号以调节IGF-1的产生。特定目的将（1）破译人GHR-STAT 5 b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）描述IGF-1产生所必需的STAT 5 b特性与免疫功能所必需的特性;（3）确定与其他细胞因子信号传导途径的串扰是否调节STAT 5 b依赖性激活IGF-1产生。然后可以产生人源化小鼠模型以重现人STAT 5 b缺陷状况。对伴有免疫缺陷的严重IGFD未解决临床病例的外显子组序列分析揭示了调节STAT 5 b作用的潜在新机制。在这些研究的结论中，该提案将确定并证实GHR-STAT 5 b相互作用特异性的机制，确定调节STAT 5 b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。

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.