A Translational Study of the Caveolin-1 Gene and Human Cardio-Metabolic Disease

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The long term objective of this proposal is for the heterogeneous disorder, metabolic syndrome, to use genomic technology to identify individuals at risk and develop individualized and targeted prevention and treatment strategies thereby, decreasing the morbidity and mortality that results from this condition. This objective is consistent with the National Institute of Nursing Research's goal to identify susceptibility genes for at-risk individuals for the design of interventions to moderate risk. Specifically, this translational proposal seeks to examine whether associations seen between the caveolin-1 gene (CAV1) and a metabolic phenotype seen in cellular and animal models, exist in humans. Specifically, CAV1 is associated with the co-aggregation of IR and HTN in humans and has been linked to an increased cardio-metabolic profile in animal models. Thus, the present proposal extends the applicability of these results in animals to humans in three ways. First, since inflammation is known to contribute to both IR and HTN, it is important to examine whether the CAV1/inflammation relationship is mediating the association of CAV1 and the co-aggregation of IR and HTN in humans. Second, the animal data suggest that the intermediate phenotype in humans is secondary to a reduction in CAV1 expression and levels. We will assess the validity of this hypothesis. Third, to assess the validity of the association of polymorphic variants of CAV1 to altered vascular function, we will assess renal blood flow by CAV1 gene variants in humans. We anticipate that individual minor allele carriers of the CAV1 variant rs926198 will have higher levels of IL-6, decreased CAV1 gene expression, and greater vascular dysfunction similar to the CAV1 animal knockout model. The proposed study begins to explore, for the first time in humans, the association between CAV1 and inflammation. Further, it examines whether the underlying physiology seen in the CAV1 knockout animal pertains to individuals with CAV1 genetic variants; translating findings from the laboratory to humans and initiating the first step of identifying more effective, nurse led individualized prevention and treatment strategies. Specifically, results from this proposal may enable nurses to use CAV1 genotype to identify individuals most at risk for the co-aggregation of IR and HTN and develop individualized educational, behavioral, and pharmacologic interventions targeting the identified physiologic pathways found to be disrupted with CAV1 variation. Further, the new techniques learned will greatly benefit the trainee in her future clinical research career studying the geneti underpinnings of complex diseases. With this knowledge the nurse practitioner will be more effective in providing individualized care.