Research Projects

Like all other non-communicable disorders, hypertension and atherosclerosis are responsible for thousands of human deaths in India and abroad annually. This is accelerated with the increase in lifestyle changes across the world. Pathophysiology of hypertensive and atherosclerotic patients are additionally complicated with co-existing renal and gastrointestinal disorders including diabetes, GI-tract infection etc. among others. While, existing therapeutic approaches to control hypertension and atherosclerosis include surgery and chemotherapy, or combination there-of, none of them, are without side-effects or completely able to cure these types of CVDs. Most of the therapeutic approaches are expensive too since once detected they are required for these patients throughout their life, thereby increasing a huge financial burden for the victims’ families which is of prime importance for the low- & middle-income families in India. Therefore, more anti-hypertensive and anti-atherosclerotic drug targets and drugs in addition to deciphering the underlying complex mechanism of these CVDs in relation to olfactory receptors OR51E2 and OR51J1 (since they work differently than existing anti-CVD drug targets) are of pivotal importance. To avoid side-effects of anti-hypertensive and anti-atherosclerotic drugs, we propose to design drugs specific for these targets for which we will apply the most successful strategy of structure-based drug designing by first investigating and validating OR51E2 and OR51J1 as the cardioprotective GPCR targets & determining their three-dimensional structures, and finally rigorous biophysical and biochemical evaluation of the compound libraries. The proposal also aims to find synthetically less expensive anti-hypertensive and anti-atherosclerotic drugs to reduce related therapeutic costs. From our ongoing study, we have observed that OR51J1 is present not only in cancer tissues but also in cardiac cells. Since, these GPCRs (i.e., OR51J1 and OR51E2) are highly conserved and rarely mutates they stands out to be novel drug targets which can be regulated at protein levels with less possibility of drug resistance. Significance and outcomes of the project: Deciphering the mechanism of OR51E2 and OR51J1 mediated regulation of blood pressure and atherosclerosis; identification & validation of upstream & downstream cardiovascular pathways related to OR51J1 & OR51E2; cracking the molecular mechanism of how OR51J1 & OR51E2 regulate the expression of these proteins; identification of the molecular pathways modulated by these novel proteins; recombinant expression & purification of OR51J1 and OR51E2; determination of three-dimensional structures of OR51J1 &/or OR51E2; identification & biochemical as well as biophysical characterization of lead molecules identified against these OR51J1 and OR51E2 to combat hypertension and atherosclerosis; in vitro, ex vivo and in vivo (in Rat & SHR) validation of the leads against OR51J1 & OR51E2 to combat CVDs.