BLR&D Research Career Scientist Award Application

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Numerous cross-sectional and longitudinal studies have established that circulating levels of testosterone decline with age in men. Likewise, human aging also results in a gradual decline in ovarian steroid production, a dramatic decline in adrenal androgens (DHEA, DHEAS), and alterations in cortisol and aldosterone production and secretion. Similar to humans, aging in experimental rodents is also associated with profound changes in the synthesis and secretion of steroid hormones, particularly testosterone. For the past 33 years or so (with almost continuous support through Merit Review funding), my laboratory has been actively involved in delineating cellular and molecular mechanisms involved in the age-related decline in steroid hormone biosynthesis and secretion, with a particular emphasis on testosterone. Our work during the past several years has established a causal link between increased reactive oxygen species formation/excessive oxidative stress and oxidative damage to the cellular machinery involved in cholesterol transport to mitochondria resulting in attenuated cholesterol transport with consequent impairment of steroidogenesis during aging. Currently, we are investigating the impact of aging-induced excessive oxidative damage to cytosolic and mitochondrial superoxide dismutase-peroxiredoxin (SOD-PRDX) antioxidant axes on the functional expression of crucial proteins involved in cholesterol transport (SNAREs) to and within the mitochondria (StAR) for the production of steroid precursor, pregnenolone. Over the years, a second major research effort of my laboratory has been and continues to be to understand how cholesterol from lipoproteins, particularly, high-density lipoprotein (HDL), is transported, processed intracellularly, and metabolized by steroidogenic tissues and cells. We are also studying how this process affects steroid hormone synthesis, reverse cholesterol transport (RCT), and atherosclerosis. Our work on HDL metabolism (funded by NIH since 1984), have led to the demonstration that the cellular delivery of HDL-cholesteryl esters (CE) into steroidogenic cells does not involve the endocytic pathway as typified by the LDL (B/E) receptor pathway. Rather, CE is taken into the cell via a `selective' pathway in a process that did not require the internalization of the entire lipoprotein particle. This selective pathway has been extensively characterized by us and it is especially important in liver and steroidogenic tissues where it delivers CE in bulk for product formation (steroid and bile acids) and biliary cholesterol secretion as a part of RCT. Scavenger receptor, class B type 1 (SR-B1) is an HDL receptor that mediates selective delivery of HDL-CEs in steroidogenic and hepatic tissues and is also implicated in the pathophysiology of RCT and atherosclerosis. At present, we are investigating the transcriptional and posttranscriptional regulation of SR-B1 and its relevance to steroidogenesis, RCT, and atherosclerosis. Currently, we are working on two additional projects. One project is focused on defining the lipid lowering and anti-hyperglycemic actions of creosote bush-derived nordihydroguaiaretic acid (NDGA). Previous work from our laboratory has shown that NDGA, has profound effects on the core components of the metabolic syndrome (MetS) including lowering of blood glucose, free fatty acids, and triglyceride (TG) levels in several models of dyslipidemia, as well as improving body weight (obesity), insulin resistance, diabetes, hypertension, and ameliorating hepatic steatosis. The current focus of this project is to elucidate the molecular mechanism by which NDGA exerts its hypolipidemic actions in the major insulin-sensitive tissues, liver, skeletal muscle, and adipose tissue, and improves dyslipidemia, insulin sensitivity and hepatic steatosis. In another project, efficacy of several dual function apoA-I mimetic peptides (Artery Therapeutics, Inc.) engineered to mimic anti- atherosclerotic and anti-diabetic functionalities, is being evaluated using several mouse models atherosclerosis, diabetes, and obesity.