Blood Pressure Regulation by the Circadian Clock Protein Per1

描述（由申请人提供）：心血管疾病是美国的首要死因，而高血压是导致死亡的主要危险因素。近三分之一的美国人患有高血压，其中大多数人患有原发性高血压，这表明缺乏明确的病因。血压和心脏功能的昼夜波动已有充分记录。众所周知，中风和心肌梗塞等心血管事件会随着昼夜节律模式达到峰值，并且与早晨血压和心率升高有关。事实上，许多生理过程都表现出昼夜节律模式，包括睡眠-觉醒周期、心跳、激素分泌和肾功能。然而，生物钟在调节这些过程中的作用尚未在分子水平上得到理解。这些研究的长期目标是确定生物钟在高血压和心血管疾病中的作用。了解这些机制可能会带来新的疾病治疗方法。我们发现生物钟蛋白 Per1 调节限速 ? 的表达。肾上皮钠亚单位 频道。我们最近发表的数据证明了 Per1 在协调调节其他几个基因中的作用，这些基因编码有助于调节肾钠重吸收的蛋白质。 Per1正向调节其产物增加钠重吸收的基因，负向调节其产物抑制钠重吸收的基因。这些数据使我们推测 Per1 的作用会导致肾脏钠重吸收，从而导致血浆容量和血压增加。与这一假设一致的是，我们已经证明，与野生型小鼠相比，缺乏功能性 Per1 的小鼠血压显着降低。总而言之，这些新发现支持了我们的中心假设，即 Per1 作为生物钟机制的一部分，通过肾钠依赖性机制调节血压。该提案的目标是通过两个具体目标来检验我们的假设。在第一个目标中，我们将使用 Per1 入核的药理学抑制剂，并评估这种治疗对 Per1 靶基因表达和血压的影响。这些研究将确定 Per1 是否是控制血压的可行目标。第二个目标是，我们将开发一种肾脏特异性 Per1 敲除小鼠，以测试 Per1 在肾脏调节血压中的作用。这些研究有可能确定治疗高血压的新靶点，并将深入了解生物钟如何调节血压的机制。

DESCRIPTION (provided by applicant): Cardiovascular disease is the leading cause of death in the United States and hypertension is the principal risk factor for this mortality. Nearly one-third of Americans are hypertensive, and the majority of these individuals have essential hypertension, which denotes the lack of a defined etiology. Circadian fluctuations in blood pressure and cardiac function are well-documented. Cardiovascular events such as stroke and myocardial infarction are known to peak with a circadian pattern and have been linked to the morning increase in blood pressure and heart rate. Indeed, many physiological processes exhibit a circadian pattern, including the sleep- wake cycle, heartbeat, hormone secretion, and renal function. However, the role of the circadian clock in the regulation of these processes is not understood at a molecular level. The long term goal of these studies is to characterize the role of the circadian clock in hypertension and cardiovascular disease. Understanding these mechanisms could lead to new disease treatments. We have found that the circadian clock protein Per1 regulates the expression of the rate-limiting ? subunit of the renal epithelial sodium channel. Our recently published data demonstrate a role for Per1 in the coordinate regulation of several additional genes that code for proteins that contribute to the regulation of renal sodium reabsorption. Per1 positively regulates genes whose products increase sodium reabsorption, and negatively regulates genes whose products inhibit sodium reabsorption. These data led us to hypothesize that Per1 action results in induction of renal sodium reabsorption with consequent increases in plasma volume and blood pressure. Consistent with this hypothesis, we have shown that mice lacking functional Per1 have dramatically lower blood pressure compared to wild type mice. Taken together, these novel findings support our central hypothesis that Per1, as part of the circadian clock mechanism, regulates blood pressure via a renal sodium-dependent mechanism. The goal of this proposal is to test our hypothesis through two specific aims. In the first aim, we will use a pharmacological inhibitor of Per1 nuclear entry and evaluate the effect of this treatment on the expression of Per1 target genes and blood pressure. These studies will determine if Per1 is a viable target for controlling blood pressure. In the second aim, we will develop a kidney-specific Per1 knockout mouse to test the role of Per1 in the regulation of blood pressure by the kidney. These studies have the potential to identify a novel target for the treatment of hypertension and will yield insight into the mechanism of how the circadian clock contributes to the regulation of blood pressure.