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.

Public Health Relevance

Identifying the associations underlying the relationship between the caveolin-1 gene (CAV1) and increased insulin resistance and hypertension will foster future research to develop and implement nurse led, patient specific rather than the current non-specific interventions for the prevention and treatment of components of the metabolic syndrome. These study findings could directly affect public health by reducing the morbidity and mortality resulting from the metabolic syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Nursing Research (NINR)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32NR013318-01
Application #
8251440
Study Section
National Institute of Nursing Research Initial Review Group (NRRC)
Program Officer
Banks, David
Project Start
2012-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
1
Fiscal Year
2012
Total Cost
$53,714
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Underwood, Patricia C; Adler, Gail K (2013) The renin angiotensin aldosterone system and insulin resistance in humans. Curr Hypertens Rep 15:59-70
Vaidya, Anand; Underwood, Patricia C; Hopkins, Paul N et al. (2013) Abnormal aldosterone physiology and cardiometabolic risk factors. Hypertension 61:886-93
Vaidya, Anand; Underwood, Patricia C; Annes, Justin P et al. (2013) The influence of sodium- and calcium-regulatory hormone interventions on adipocytokines in obesity and diabetes. Metabolism 62:539-47