Optimizing Testis Transplantation to Study RET Signaling

优化睾丸移植以研究 RET 信号转导

• 批准号: 6812417
• 负责人: CATHY K NAUGHTON
• 金额: $ 7.65万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-09 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6812417
• 关键词: apoptosis; biological models; biological signal transduction; cell differentiation; cell growth regulation; cell proliferation; genetically modified animals; growth factor receptors; hormone regulation /control mechanism; intermolecular interaction; laboratory mouse; model design /development; pituitary hormones; protein structure function; protein tyrosine kinase; reproductive development; reproductive tissue transplantation; sperm; spermatogenesis; testis; transplantation immunology

DESCRIPTION (provided by applicant): The overall purpose of this study is to optimize whole testes transplantation technology to study Ret-mediated spermatogenesis. This technology has been used to mature testicular germ cells into spermatozoa, which have the ability to cause fertilization by intracytoplasmic sperm injection into species-specific oocytes. However, transplant efficiency of the donor testicle is not perfect as not all immature germ cells in the seminiferous tubules display complete maturation to spermatozoa. The specific aims of this proposal are to first optimize donor graft efficiency of whole testes transplantation technology and then to use it in a novel application to study important genes involved in postnatal testicular germ cell maturation. Ret is a tyrosine kinase receptor that utilizes a coreceptor and ligand to mediate downstream cellular responses including cell survival, proliferation, and differentiation. This gene is critical for postnatal germ cell maturation; however, the available deficient mouse models have been limited in studying postnatal events such as spermatogenesis, due to perinatal lethality. Whole testes tissue transplant technology will provide an opportunity to use these mouse models to study postnatal spermatogenesis for the first time. The optimization of this technique is important to achieve not only as a tool for our planned studies involving Ret, but for its potential impact on clinical and other research applications. If germ cell maturation can be conducted at a high efficiency rate, this technique will more readily be applicable to human germ cell maturation protocols involving cryopreservation of immature, prepubertal testes tissue prior to gonadotoxic chemotherapy. The clinical impact of this technology will be tremendous, as it will provide a pre-treatment option presently not available for pediatric male cancer patients who may become permanently sterile. Determining how Ret affects testicular function will add to our understanding of human male infertility and may provide an avenue for new treatment strategies for infertile men with nonobstructive azoospermia.

描述（由申请人提供）：本研究的总体目的是优化整个睾丸移植技术以研究RET介导的精子发生。该技术已被用于成熟的睾丸生殖细胞进入精子中，这些生殖细胞具有通过胞质内精子注射到物种特异性卵母细胞中的受精的能力。但是，供体睾丸的移植效率并不完美，因为并非所有未成熟的生殖细胞中的所有未成熟生殖细胞都表现出完全成熟到精子中。该建议的具体目的是首先优化整个睾丸移植技术的供体移植效率，然后在新的应用中使用它来研究参与产后睾丸生殖细胞成熟的重要基因。 RET是一种酪氨酸激酶受体，它利用共感受器和配体介导下游细胞反应，包括细胞存活，增殖和分化。该基因对于产后生殖细胞成熟至关重要。但是，由于围产期致死性，可用的缺陷小鼠模型在研究产后事件（例如精子发生）方面受到限制。整个睾丸组织移植技术将为使用这些小鼠模型首次研究产后生理发生提供机会。该技术的优化对于我们计划的RET研究的工具，而且对其对临床和其他研究应用的潜在影响都非常重要。如果可以以高效率速率进行生殖细胞成熟，则该技术将更容易适用于人类生殖细胞成熟方案，涉及涉及未成熟的冷冻保存，前青春期前睾丸在进行性腺毒性化疗之前会组织组织。该技术的临床影响将是巨大的，因为它将为可能永久无菌的小儿男性癌症患者提供一种预处理的选择。确定RET如何影响睾丸功能将增加我们对男性不育症的理解，并可能为具有非刺激性无偶像性植物的不育男性提供新的治疗策略途径。