1. Cardiac consequences of prenatal cocaine exposure: The central hypotheses of the proposal are: i) that prenatal cocaine exposure induces cardiac myocyte apoptosis through activation of JNK/p38 MAPK-mediated mitochondria-dependent pathway and ii) minocycline, through inhibition of this signal transduction pathway, will confer protection in cardiac myocyte death induced by prenatal cocaine exposure. Specific aims contain characterization of the key molecular components of the JNK/p38-mediated apoptotic pathway in myocyte death and its mitigation by minocycline or JNK inhibitor. Results of this study will provide insight into the underlying mechanism of cardiac myocyte death that occurs in offspring after prenatal cocaine exposure. Identifying signaling pathways leading to myocyte death paves the way to design therapeutic remedies to myocyte death and, in turn, cardiac consequences of prenatal cocaine exposure.
2. Molecular Mechanism of Sarcopenia and its Prevention: Sarcopenia is defined as the progressive decline of skeletal muscle mass and strength, which occurs with aging. I was able to show for the first time that testosterone-induced increase in muscle size is associated with fiber hypertrophy and significant increases in myonuclear and satellite cell numbers in both young and old men (Sinha-Hikim et al., Am J Physiol Endocrinol Metab 2002, 2003; Sinha-Hikim et al., J Clin Endocrinol Metab 2006). My laboratory, using mouse models, has provided new insights into the molecular mechanisms of muscle cell apoptosis (Sinha-Hikim et al, Apoptosis, 2007; Braga et al., Apoptosis, 2008). We were also the first team to provide mechanistic insights by which testosterone supplement may induce skeletal muscle fiber hypertrophy (Brown et al, J Endocrinol, 2009; Kovacheva et al., Endocrinology, 2010). This information is crucial for understanding the skeletal muscle pathophysiology in aging and for further research directed toward clinical management of successful aging, which could lay a foundation based on which rational hormone replacement therapy could be designed for delaying or preventing loss of muscle mass in elderly men as well as in other wasting states.
3. Use of a Novel Antioxidant as a Part of Dietary supplement: The search for natural products that are culturally acceptable and understanding their mechanisms of action is a critical component in the fight to reduce health disparities and improve the overall health of the nation. Nonalcoholic fatty liver disease (NFLD) includes the whole spectrum of fatty liver, including steatosis, steatohepatitis, and cirrhosis. Oxidative stress is pivotal in the pathogenesis of NFLD. We examined the effects of a novel cystine based glutathione precursor fortified with selenium (FT061452 TM or F1) in preventing steatosis in ApoE-/- mice fed with high-fat diet. The results demonstrate that dietary supplementation of F1, a modified glutathione precursor prevents high fat diet-induced induced steatosis in ApoE-/- mice and emphasizes the suitability of this model for investigating the mechanisms of diet-induced steatosis.