C-Ros pathways as targets for contraceptive development

性状（由申请方提供）：附睾在精子成熟过程中起着至关重要的作用，因此被认为是开发男性避孕药的主要靶点。我们的策略是靶向附睾内对男性生育力至关重要的受体、激酶和磷酸酶。这些靶点是理想的，因为它们适合于小分子量抑制剂，并且血液-附睾屏障不会成为此类抑制剂的强大障碍。考虑到这些策略，我们的目标是研究孤儿酪氨酸激酶受体c-Ros作为男性避孕药开发的目标。我们也有兴趣在确定的上游监管机构和下游目标的c-Ros男性避孕药的发展目标的组成部分。选择C-Ros是因为c-Ros敲除的雄性小鼠是不育的。本研究的具体目的是：（1）验证调控c-Ros的表达和活性可以调节成年雄性小鼠生育力的假设。为了实现这一特定目标，我们将在小鼠的初始片段中产生新的条件性c-Ros敲除。(2)验证c-Ros的活性依赖于其激酶结构域与其他结合蛋白（包括新的和已知的激酶和磷酸酶）的结合的假设。与c-Ros活性相关的蛋白质将被视为男性避孕药开发的靶点。我们将产生SHP-1磷酸酶的初始片段特异性条件性敲除，其与c-Ros的激酶结构域结合。(3)为了检验c-Ros的活性依赖于其胞外结构域与膜结合受体的结合的假设。我们将产生代谢型谷氨酸受体样孤儿G蛋白偶联受体的初始片段特异性条件性敲除，该受体是c-Ros的推定配体。将鉴定在每只推定不育基因敲除动物的初始片段中发生变化的下游激酶、磷酸酶和受体的表达和活性，并进一步考虑将其作为避孕药开发的靶点。因此，根据RFA的研究范围，我们将进行“精子成熟过程的研究，目的是确定特定的目标，涉及男性生育力的控制。"

DESCRIPTION (provided by applicant): The epididymis plays a crucial role in the maturation of spermatozoa and is, therefore, considered to be a prime target for the development of a male contraceptive. Our strategy is to target receptors, kinases and phosphatases within the epididymis that are crucial for male fertility. These targets are ideal because they are amenable to small molecular weight inhibitors and the blood-epididymis barrier would not be a formidable hurdle for such inhibitors. With these strategies in mind, our goal is to examine the orphan tyrosine kinase receptor c-Ros as a target for male contraceptive development. We are also interested in identifying the components of upstream regulators and downstream targets of c-Ros as targets for male contraceptive development. C-Ros was chosen because c-Ros knockout male mice are infertile. The specific aims of this proposal are: (1) To test the hypothesis that modulating the expression and activity of c-Ros can regulate fertility in adult male mice. To accomplish this specific aim we will generate a novel conditional c-Ros knockout in the initial segment of mice. (2) To test the hypothesis that the activity of c-Ros is dependent upon the association of its kinase domain with other binding proteins including novel and known kinases and phosphatases. Proteins that associate with c-Ros activity will be considered as targets for the development of a male contraceptive. We will generate an initial segment-specific conditional knockout of the SHP-1 phosphatase, which binds to the kinase domain of c-Ros. (3) To test the hypothesis that the activity of c-Ros is dependent upon its association of its extracellular domain with a membrane-bound receptor. We will generate an initial segment-specific conditional knockout of the metabotropic glutamate receptor-like orphan G-protein coupled receptor, which is the putative ligand for c-Ros. Expression and activity of downstream kinases, phosphatases and receptors that change in the initial segment of each putative infertile knockout animal will be identified and considered further as targets for contraceptive development. Therefore, in accordance with the research scope of the RFA, we will perform "research on the processes of sperm maturation with the goal of defining specific targets, involved in the control of male fertility."