Research Projects

Cardiovascular diseases (CVDs) remain the foremost cause of global mortality, with myocardial infarction (MI) and ischemic stroke accounting for a substantial share. Central to these pathologies is hypoxia-driven tissue damage, which leads to oxidative stress, endothelial dysfunction, and metabolic derangement. Despite decades of research into hypoxia biology, effective therapies remain limited, and inter-individual variability in hypoxia response is still poorly understood. Interestingly, certain high-altitude human populations exhibit remarkable resilience to chronic-hypoxia, suggesting the presence of genetically mediated adaptive mechanisms [1-3]. The Gujjar Bakarwal (GB) community of Jammu & Kashmir represents one such distinct and largely unexplored population. With a population exceeding 1.5 million, they constitute over 70% of the Scheduled Tribe population in the region, which itself comprises approximately 12% of Jammu Kashmir’s total population [4, 5]. Traditionally pastoral and semi-nomadic, they undertake seasonal transhumance across altitudes ranging from the lowland plains (~500m) to alpine pastures exceeding 2,500 m. Despite chronic exposure to hypobaric hypoxia and environmental extremes, these individuals exhibit a surprisingly low incidence of hypertension, anemia, and ischemic heart failure[6-9]. This resilience suggests the existence of naturally selected genetic variants that confer cardiopulmonary and metabolic protection. However, this population remains severely underrepresented in India’s genomic research landscape, presenting a significant scientific and translational gap. This proposal is based on hypothesis that the Gujjar Bakarwal population harbors protective variants in key hypoxia-regulated genes particularly those in the AKT-MTOR-HIF signaling axis and associated metabolic, vascular, and stress response pathways. These include genes such as HIF1A, EPAS1, EGLN1, AKT1, MTOR, AMPK, VEGFA, NOS3, ARG1, ATF4, and EIF2AK3, which play pivotal roles in orchestrating oxygen sensing, redox regulation, nitric oxide signaling, angiogenesis, and endoplasmic reticulum (ER) stress responses. Such variants may fine-tune transcriptional and translational responses to low oxygen and could also influence responsiveness to pharmacological agents that target the same pathways. The study will adopt a multitiered systems approach involving clinical phenotyping, biochemical profiling, protein quantification (ELISA), gene expression analysis, targeted DNA sequencing of mutational hotspots, and functional validation through in vitro cell based assays under hypoxic and pharmacological exposure. By comparing the GB population with matched lowland tribal and nontribal controls, the study design effectively controls for both genetic ancestry and environmental exposure, thereby enabling stronger causal inference. What makes this study both novel and timely is its integration of diverse data layers genomic, transcriptomic, proteomic and cellular within a single understudied tribal cohort. Importantly, it goes beyond mere associations to mechanistically validate how identified variants functionally impact hypoxia adaptation and drug response. The anticipated outcomes of this project are two-fold: (i) To elucidate evolutionarily fine-tuned molecular strategies that underpin hypoxia resilience (ii) To identify genetic leads that may inform population specific or personalized therapeutic strategies for ischemia driven conditions.