Biological Role of a Novel Testis Insulin-Like Protein

新型睾丸胰岛素样蛋白的生物学作用

• 批准号: 6801808
• 负责人: Ram K. Menon
• 金额: $ 7.65万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-15 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6801808
• 关键词: clinical research; family genetics; fertility; gene mutation; gene targeting; genetically modified animals; genotype; hormone regulation /control mechanism; human genetic material tag; human subject; insulin receptor; insulinlike factor; intracellular transport; laboratory mouse; male; phenotype; protein transport; reproductive development; sperm analysis; testis

DESCRIPTION (provided by applicant): The proteins of the insulin family play essential roles in pleotropic physiological processes affecting metabolism, growth, and reproduction. Using the techniques of molecular and computational biology our laboratory recently identified a novel member of the insulin family we termed Insl6 (insulin-like protein 6). Expression of Insl6 is greatest in germ cells of the testis. Evolutionary conservation of the structure of the Insl6 gene suggests an essential biological role for this protein. However, at present the biological role of Insl6 is not known. Our preliminary studies have identified a subject with male infertility with a heterozygous mutation in the INSL6 gene. Our studies indicate that the identified mutation alters the intra-cellular trafficking of the Insl6 protein. Specific Aim 1 expands on these observations and tests the hypothesis that mutations in the INSL6 gene are associated with characteristic phenotypes in the human. The genotype-phenotype correlation will be established by analysis of clinical history, physical examination, sperm analysis, and endocrine profile. Specific Aim 2 tests the hypothesis that the Insl6 null phenotype, generated by targeted disruption of the murine Insl6 gene, will reflect the biological role of Insl6. The Insl6 null mice will be evaluated for phenotypic characteristics including viability, sexual differentiation, fertility, testicular macro- and microstructure, sperm analysis, and endocrine profile. The identification of new members of the insulin gene family has led to the elucidation of novel functions for this family of proteins. For example, targeted disruption of insulin-like peptide 3 (Insl3) in the mouse revealed a critical role for this peptide in testicular descent. Furthermore, the recent discovery of the cognate receptor (LGR8) for Insl3 and the elucidation of cryptorchidism as one of components of the LGR8 null phenotype underscore the exciting advances made in this field. The results from experiments outlined in this proposal will advance our understanding of the biological role of Insl6 and provide insights into human reproduction and disorders such as infertility.

性状（由申请方提供）：胰岛素家族蛋白在影响代谢、生长和生殖的多效性生理过程中发挥重要作用。利用分子和计算生物学技术，我们的实验室最近确定了一个新的胰岛素家族成员，我们称之为Insl 6（胰岛素样蛋白6）。Insl 6在睾丸生殖细胞中的表达最高。Insl 6基因结构的进化保守性表明这种蛋白质具有重要的生物学作用。然而，目前Insl 6的生物学作用尚不清楚。我们的初步研究已经确定了一个受试者与INSL 6基因杂合突变的男性不育症。我们的研究表明，所鉴定的突变改变了Insl 6蛋白的细胞内运输。具体目标1扩展了这些观察结果，并测试了INSL 6基因突变与人类特征表型相关的假设。将通过分析临床病史、体格检查、精子分析和内分泌特征来确定基因型-表型相关性。特定目的2检验了通过鼠Insl 6基因的靶向破坏产生的Insl 6无效表型将反映Insl 6的生物学作用的假设。将评价Insl 6缺失小鼠的表型特征，包括活力、性分化、生育力、睾丸宏观和微观结构、精子分析和内分泌特征。 胰岛素基因家族新成员的鉴定导致了该蛋白质家族新功能的阐明。例如，在小鼠中靶向破坏胰岛素样肽3（Insl 3）揭示了这种肽在睾丸下降中的关键作用。此外，最近发现的同源受体（LGR 8）的Insl 3和隐睾症的阐明作为一个组成部分的LGR 8无效表型强调了令人兴奋的进展，在这一领域。该提案中概述的实验结果将促进我们对Insl 6生物学作用的理解，并为人类生殖和不孕症等疾病提供见解。