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."""""""" ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HD045890-02
Application #
6831200
Study Section
Special Emphasis Panel (ZHD1-DRG-D (28))
Program Officer
Blithe, Diana
Project Start
2003-12-01
Project End
2008-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
2
Fiscal Year
2005
Total Cost
$220,375
Indirect Cost
Name
University of Virginia
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904