The Role of RET in Spermatogenesis

RET 在精子发生中的作用

• 批准号: 6788098
• 负责人: CATHY K NAUGHTON
• 金额: $ 12.03万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-07 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6788098
• 关键词: biological signal transduction; cell differentiation; cell type; clinical research; enzyme activity; fertility; human tissue; immunocytochemistry; laboratory mouse; protein isoforms; protein structure function; protein tyrosine kinase; receptor expression; spermatogenesis; terminal nick end labeling

DESCRIPTION (provided by applicant): The two objectives of this application are to support my training as a physician-scientist and to establish the importance of RET tyrosine kinase and its coreceptors and ligands in spermatogenesis. This award will facilitate my transition into an independent investigator by providing molecular laboratory training under the mentorship of Dr. Jeffrey Milbrandt, Professor of Pathology and Immunology and Internal Medicine at Washington University School of Medicine. Dr. Milbrandt is ideally suited to be my mentor for several reasons. His laboratory has significant experience in studying RET, its coreceptors and ligands and has all the available resources, including mouse models, antibodies, probes, etc., already in place to facilitate successful completion of the proposed application. He has previously served as research mentor to eight, K08 recipients in the past 10 years. I will receive continuity of training, as I have previously worked in his laboratory for three years. A didactic program in molecular biology will complement the intellectual environment provided by Dr. Milbrandt's laboratory, the Siteman Cancer Center Developmental Biology Research Meetings, and the Division of Urologic Surgery Research Conferences. The importance of RET, its coreceptors and ligands in spermatogenesis is evidenced by testis expression studies, abnormalities in spermatogenesis of mouse models with mutations of the RET receptor, and loss of RET protein expression in human cases of maturation arrest and male infertility. Maturation arrest is a cause of male-factor infertility due to failure of existing testicular germ cells to mature. Presently, there is no therapy for these patients, and the only potential option for these couples for their own biological children is in vitro fertilization with intracytoplasmic sperm injection. Identification of the component(s) responsible for continued sperm maturation in these men is first necessary in order to target future therapies to facilitate sperm maturation in vivo. The specific aims of this proposal will explore the role of RET in spermatogenesis to determine if signaling through RET is important for germ cell survival, proliferation, and/or maturation. This will be accomplished by studying the disturbed spermatogenesis identified in a mouse model carrying a mutation of the RET receptor. The translation to human disease will be achieved by studying RET expression in male infertility cases of maturation arrest.

描述（由申请人提供）：本申请的两个目标是支持我作为医师科学家的培训，并确定RET酪氨酸激酶及其共受体和配体在精子发生中的重要性。该奖项将通过在华盛顿大学医学院的病理学和免疫学和内科教授Jeffrey Milbrandt博士的指导下提供分子实验室培训来促进我向独立研究者的过渡。米尔布兰特博士非常适合成为我的导师，原因有几个。他的实验室在研究RET，其共感受器和配体方面具有丰富的经验，并且拥有所有可用资源，包括鼠标模型，抗体，探针等，以促进成功完成拟议的应用。在过去的10年中，他以前曾担任八名K08接收者的研究导师。我将获得培训的连续性，因为我以前在他的实验室工作了三年。分子生物学的教学计划将补充米尔布兰特博士实验室，现场癌症中心发育生物学研究会议和泌尿外科手术研究会议的智力环境。 睾丸表达研究，具有RET受体突变的小鼠模型的精子发生中的异常证明了RET的重要性，其共受体和配体在精子发生中的重要性，而在人类成熟的病例中，RET蛋白表达的丧失和男性不育症的丧失。由于现有的睾丸生殖细胞未能成熟，成熟停滞是男性因素不育症的原因。目前，这些患者没有治疗，这些夫妻对自己的亲生儿童的唯一潜在选择是在体外受精，胞质内精子注射。为了靶向将来的疗法以促进体内精子成熟，首先需要确定这些男性持续成熟的成分的鉴定。该提案的具体目的将探讨RET在精子发生中的作用，以确定通过RET信号传导对于生殖细胞存活，增殖和/或成熟是否重要。这将通过研究携带RET受体突变的小鼠模型中鉴定出的精子发生来实现。通过研究男性不育症病例中的RET表达来实现人类疾病的翻译。