The primary goal of my research is to determine and understand the function of lactate dehydrogenase C4 (LCH- C4) in the mammalian testis. Achieving this goal should increase our fundamental knowledge about the molecular basis of spermatogenesis. Many germ cell proteins and enzymes have been described, but few are as well defined functionally as LDH- C4, which is a key metabolic enzyme with an important catalytic function during spermatogenesis and in spermatozoa. Many studies over the past several years have confirmed that spermatocyte metabolism prefers lactate from Sertoli Cells as a primary energy source. Glycolysis is the preferred route of substrate utilization by sperm. There is now surprising evidence that the function of LDH-C4 in sperm maturation may go beyond the enzymatic to a structural role in the sperm and a regulatory role in the germinal epithelium. These findings support my hypothesis that LDH-C4 is required for both the completion of spermatogenesis and for sperm function. My laboratory has contributed to the structural, biochemical and molecular characterization of this isozyme and more recently to a description of cis and trans elements regulating expression of the cognate gene in primary spermatocytes. This in depth analysis provides the platform for experimentation on the function of this protein itself and as a model in the molecular analysis of spermatogenesis. Our rationale is that understanding the regulation of Idhc expression relates to its specialized function as a cell specific protein and further that the regulatory mechanisms are likely to reflect those responsible for activating genes generally essential to spermatogenesis.
The specific aims of this proposal are: 1) identify and characterize the transcription factor(s) responsible for germ cell specific expression of ldhc; 2) to target disruption of the ldhc gene in mice; 3) to describe both catalytic and non-catalytic functions of LDH-C4 in testis and sperm, identifying protein-protein interactions that tether LDH-C4 to the fibrous sheath, and protein-nucleic acid interactions that may regulate testis gene translation. Completion of these specific aims will further our understanding of LDH-C4 function, of testis specific gene regulation and of macromolecular interactions necessary for normal spermatogenesis and sperm function. ? ?
