In the new grant period we will utilize the information we have extracted from our large microarray databasesto focus on the process of spermatogonial maturation and the role of retinoids in that process. Our array dataclearly identifies a retinoid responsive gene, termed StraS, that is expressed in germ cells of the postnatalmale and embryonic female as a precursor to entry into meiosis. Previous work in our laboratory and otherlaboratories has shown that a vitamin A deficiency blocks the conversion of undifferentiated spermatogoniato differentiating A1 spermatogonia. This observation suggests retinoic acid is required for theundifferentiated spermatogonia to enter into a differentiation pathway and ultimately into meiosis. Inductionof the gene, StraS, is a requirement and a reliable marker for this process. The action of retinoic acid andthe subsequent changes in gene expression that occur, dramatically impact the maturation of spermatogoniaand the onset of meiosis. Major parts of the proposed project are to more clearly define the response ofspermatogonia to retinoic acid, to examine the response of the StraS gene in detail and to find other genesinvolved in the maturation process. In particular, we will focus on the potential role of 3 additional genes,Tex13, Xlr4 and an EST no. 1700013H16Rik which all share a pattern of expression that mirrors that ofStraS.
Three specific aims are proposed: 1. Define the retinoic acid response of the testis with regard to thesomatic cells and the maturation of spermatogonia. 2. Define the transcriptional elements that regulate StraSexpression and spermatogonial maturation. 3. Determine the cellular localization and direct interactingpartners of StraS, Tex13, Xlr4 and 1700013H16Rik in spermatocytes. This research project couldpotentially determine the molecular mechanisms that initiate spermatogenesis in the male germline.Knowledge about the actions of retinoic acid and the genes responsible for the entry of spermatogonia intothe differentiation pathway could lead to new approaches to contraception.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
2U54HD042454-06
Application #
7284605
Study Section
Special Emphasis Panel (ZHD1-DSR-A (14))
Project Start
2007-03-01
Project End
2012-02-29
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
6
Fiscal Year
2007
Total Cost
$363,729
Indirect Cost
Name
University of Washington
Department
Type
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Berkseth, Kathryn E; Rubinow, Katya B; Melhorn, Susan J et al. (2018) Hypothalamic Gliosis by MRI and Visceral Fat Mass Negatively Correlate with Plasma Testosterone Concentrations in Healthy Men. Obesity (Silver Spring) 26:1898-1904
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Paik, Jisun; Treuting, Piper M; Haenisch, Michael et al. (2018) Can inhibition of retinoic acid biosynthesis function as a non-hormonal female contraceptive? Contraception :
Sharma, Manju; Braun, Robert E (2018) Cyclical expression of GDNF is required for spermatogonial stem cell homeostasis. Development 145:
Rubinow, Katya B; Vaisar, Tomas; Chao, Jing H et al. (2018) Sex steroids mediate discrete effects on HDL cholesterol efflux capacity and particle concentration in healthy men. J Clin Lipidol 12:1072-1082
Haenisch, Michael; Treuting, Piper M; Brabb, Thea et al. (2018) Pharmacological inhibition of ALDH1A enzymes suppresses weight gain in a mouse model of diet-induced obesity. Obes Res Clin Pract 12:93-101
Swerdloff, Ronald S; Dudley, Robert E; Page, Stephanie T et al. (2017) Dihydrotestosterone: Biochemistry, Physiology, and Clinical Implications of Elevated Blood Levels. Endocr Rev 38:220-254
Ayoub, R; Page, S T; Swerdloff, R S et al. (2017) Comparison of the single dose pharmacokinetics, pharmacodynamics, and safety of two novel oral formulations of dimethandrolone undecanoate (DMAU): a potential oral, male contraceptive. Andrology 5:278-285
Rubinow, Katya B; Chao, Jing H; Hagman, Derek et al. (2017) Circulating sex steroids coregulate adipose tissue immune cell populations in healthy men. Am J Physiol Endocrinol Metab 313:E528-E539

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