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

该提案的长期目标是针对异质性疾病代谢综合征，使用基因组技术来识别风险个体，并制定个体化和有针对性的预防和治疗策略，从而降低由这种情况导致的发病率和死亡率。这一目标与国家护理研究所的目标是一致的，以确定易感基因的风险个体的干预措施，以中度风险的设计。具体来说，这项翻译建议旨在研究caveolin-1基因（CAV 1）与细胞和动物模型中观察到的代谢表型之间的关联是否存在于人类中。具体而言，CAV 1与人类中IR和HTN的共聚集相关，并与动物模型中增加的心脏代谢特征相关。因此，本提案以三种方式将这些结果在动物中的适用性扩展到人类。首先，由于已知炎症会导致IR和HTN，因此重要的是检查CAV 1/炎症关系是否介导CAV 1与IR和HTN在人体中的共聚集的关联。其次，动物数据表明，人类的中间表型是继发于CAV 1表达和水平的降低。我们将评估这一假设的有效性。第三，为了评估CAV 1多态性变异与血管功能改变相关性的有效性，我们将通过人类CAV 1基因变异评估肾血流量。我们预计，与CAV 1基因敲除动物模型相似，CAV 1变异体rs 926198的单个次要等位基因携带者将具有更高水平的IL-6、降低的CAV 1基因表达和更大的血管功能障碍。这项研究首次在人类中探索了CAV 1与炎症之间的关联。此外，它还检查了在CAV 1基因敲除动物中观察到的潜在生理学是否与CAV 1遗传变异个体有关;将实验室的发现转化为人类，并启动识别更有效的第一步，护士领导的个性化预防和治疗策略。具体而言，从这个建议的结果可能使护士使用CAV 1基因型，以确定个人的IR和HTN的共聚集的风险最大，并制定个性化的教育，行为和药理学干预措施，针对已确定的生理途径被破坏与CAV 1变异。此外，学到的新技术将极大地有利于她未来的临床研究生涯研究复杂疾病的遗传基础的受训者。有了这些知识，执业护士将更有效地提供个性化护理。

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.