Grant: Operating Grant

Eukaryotic steroid hormones are responsible for the maintenance of the organism's homeostasis, adaptability to the environment, and developmental and reproductive functions. Many tissues of the body have the ability to metabolize steroids. However, few tissues are able to synthesize steroid hormones from the substrate cholesterol. These tissues are the gonads, adrenals, placenta and brain. Steroid synthesis begins with the transport of the substrate cholesterol from intracellular stores into mitochondria to be converted to pregnenolone. Translocator protein (TSPO), formerly known as peripheral-type benzodiazepine receptor, is a ubiquitous drug- and cholesterol-binding protein found primarily in the outer mitochondrial membrane. Although TSPO is found in many tissues, it is expressed at the highest levels in steroid synthesizing cells. Using a combination of biochemical, pharmacological and molecular approaches, as well as animal models, we will test the hypotheses that (i) changes in TSPO organization and levels in the mitochondria determine the amount of cholesterol available for testosterone synthesis in Leydig cells, the testosterone-producing cells of the testis, ultimately affecting testicular function, and (ii) pharmacological activation of TSPO can lead to a direct induction of androgen formation. The proposed studies aim to unveil the structure and regulation of expression of the Tspo gene as well as to develop novel pharmacological means to induce androgen formation in vivo. Elucidation of the mechanisms underlying steroid synthesis is critical to understanding the origin of diseases associated with reduced androgen formation, including infertility and metabolic syndrome, and developing novel therapies for their treatment. These studies will also pave the way for the development of novel pharmacological strategies for manipulation of the adrenal and brain function, tissues where TSPO plays a regulatory role in corticosteroid and neurosteroid formation.