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

这项建议的长期目标是针对异质性疾病代谢综合征，利用基因组技术识别风险个体，并制定个性化和有针对性的预防和治疗策略，从而降低这种疾病造成的发病率和死亡率。这一目标与国家护理研究所的目标一致，即确定高危个体的易感基因，以设计适度风险的干预措施。具体地说，这项翻译建议试图检查在细胞和动物模型中看到的小窝蛋白-1基因(CAV1)和代谢表型之间的关联是否存在于人类中。具体地说，CAV1与IR和HTN在人类中的共同聚集有关，并与动物模型中心脏代谢特征的增加有关。因此，本提案在三个方面将这些结果在动物身上的适用性扩展到了人类。首先，由于已知炎症对IR和HTN都有贡献，因此很重要的一点是检查CAV1/炎症关系是否介导了CAV1的关联以及IR和HTN在人类中的共同聚集。其次，动物数据表明，人类的中间表型仅次于CAV1的表达和水平的降低。我们将评估这一假设的正确性。第三，为了评估CAV1多态变异与血管功能改变的关联的有效性，我们将通过CAV1基因变异来评估人类的肾脏血流量。我们预计CAV1变异rs926198的个体微小等位基因携带者将具有更高的IL-6水平，降低CAV1基因的表达，以及更大的血管功能障碍，类似于CAV1动物基因敲除模型。这项拟议的研究首次在人类身上探索CAV1与炎症之间的联系。此外，它还检查在CAV1基因敲除动物中看到的潜在生理学是否与携带CAV1基因变异的个体有关；将实验室的发现转化为人类，并启动确定更有效的、由护士领导的个性化预防和治疗策略的第一步。具体地说，这项建议的结果可能使护士能够使用CAV1基因型来识别IR和HTN共同聚集的最高风险个体，并针对已发现的CAV1变异扰乱的生理通路开发个性化的教育、行为和药物干预措施。此外，学习到的新技术将极大地帮助学员在未来的临床研究生涯中研究复杂疾病的Geneti基础。有了这些知识，护士从业者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.