Coupling Factor 6 in Cold-induced Kidney Dysfunction and Hypertension

 描述（由申请人提供）：有充分的证据表明，居住在寒冷地区的人高血压和相关心血管疾病的患病率增加。事实上，寒冷的温度会增加血压（BP）。在美国，心血管疾病的发病率和死亡率最高发生在寒冷的冬季。寒冷的气温使高血压加重，并引发高血压患者的心肌梗死和中风。间歇性暴露于中度寒冷（5°C）会在三周内导致小鼠和大鼠的高血压，即冷诱导性高血压（CIH）。我们的长期目标是了解低温如何导致高血压和相关心血管疾病，以便制定预防和治疗策略。本申请的目的是评估偶联因子6（CF6）（ATP合酶的亚基）的上调是否有助于冷诱导的盐敏感性、血管功能障碍和CIH。中心假设是，间歇性暴露于冷上调CF6，这损害钠排泄，并导致血管功能障碍，从而导致CIH。这一目标将通过追求三个互补的具体目标，使用几种新的方法，包括在体内细胞特异性基因传递，内皮细胞特异性基因敲除，和实时监测血压（遥测）的组合。具体目标是：（1）确定CF6的上调是否损害肾Na排泄（盐敏感性）并引起促成CIH的血管功能障碍。(2)研究CF6在冷诱导的肾钠排泄损伤中介导作用的分子机制。(3)研究CF6在冷诱导的血管功能障碍中的分子机制。这些研究结果将揭示CF6在调节肾钠排泄和血管功能方面的新作用，这是以前未发现的。完成拟议的研究将使我们处于一个突出的位置，以制定针对CF6的高血压预防和治疗策略。因此，拟议的工作是创新和重要的，因为它利用最先进的方法来解决与冷应激相关的重要医学问题，该问题影响了大量人口，但仍缺乏探索。

 DESCRIPTION (provided by applicant): It is well documented that people who live in cold regions have increased prevalence of hypertension and related cardiovascular diseases. Indeed, cold temperatures increase blood pressure (BP). In the US, the highest morbidity and mortality due to cardiovascular disease occur during the cold winter season. Cold temperatures make hypertension severer and trigger myocardial infarction and stroke in hypertensive patients. Intermittent exposure to moderate cold (5°C) causes hypertension in mice and rats within three weeks, namely cold-induced hypertension (CIH). Our long-term goal is to understand how cold temperatures cause hypertension and related cardiovascular diseases in order to develop preventive and therapeutic strategies. The objective of this application is to assess if upregulation of coupling factor 6 (CF6), a subunit of ATP synthase, contributes to cold-induced salt sensitivity, vascular dysfunction, and CIH. The central hypothesis is that intermittent exposure to cold upregulates CF6 which impairs Na excretion and causes vascular dysfunction contributing to CIH. The objective will be achieved by pursuing three complementary specific aims using a combination of several novel approaches including in vivo cell-specific gene delivery, endothelial cell-specific gene knockout, and real-time monitoring of blood pressure (telemetry). The specific aims are: (1) Determine if the upregulation of CF6 impairs renal Na excretion (salt sensitivity) and causes vascular dysfunction contributing to CIH. (2) Investigate the molecular mechanism that mediates the role of CF6 in cold-induced impairment in renal Na excretion. (3) Investigate the molecular mechanism that mediates the role of CF6 in cold- induced vascular dysfunction. The findings from the proposed studies will reveal novel roles of CF6 in regulating renal Na excretion and vascular function which were previously unidentified. Completion of the proposed research will put us in an outstanding position to develop preventive and therapeutic strategies for hypertension by targeting CF6. Therefore, the proposed work is innovative and significant because it utilizes state-of-the-art approaches to addresses an important medical problem associated with cold stress which affects a large population but remains poorly explored.