Physiological Role of Activation of the JAK/STAT pathway in Hypertension

项目总结(见说明)： 数据表明，一条信号通路可能与糖尿病的不良后果有关 高血压是JAK/STAT途径。我们的数据支持这样一种观点，即该通路的激活对 血管紧张素Ⅱ在高盐和高剂量血管紧张素Ⅱ(正常盐)模型上引起H3T升高的能力。 初步数据进一步表明，JAK2似乎在人类利用的分子机制中发挥了关键作用 血管紧张素II可引起血管收缩。这些研究表明，JAK2活性抑制物的变化， SHP-1可能参与了JAK2的激活。此外，在体内，去甲肾上腺素也能激活 提示JAK2可能是引起血压升高的常见因素。 因此，我们建议检验JAK/STAT通路在体内激活的假设 高血压导致血管内皮功能障碍和肾脏并发症的发展 通过肾小球滤过率(GFR)、肾血流量和肾小球发育的变化来评估 硬化症。这些拟议的研究的目标是使用一种综合的方法结合整个动物 生理学通过对细胞内信号机制的生化分析来阐明分子 参与并发症发生的机制。为了实现这一目标，我们提出了三个具体的建议 目标。具体目标1：确定在DOCA-SALT中是否激活了JAK/STAT通路的相同成员， Ang Il-高盐和去甲肾上腺素诱导的高血压模型。具体目标2：确定高血压对 胞浆蛋白酪氨酸磷酸酶、SHP-1、SHP-2和PTP-IB以及C3rtokine抑制因子的作用 调节JAK/STAT通路的信号(SoC)。具体目标3：确定JAK/STAT的相互作用 与高血压有关的其他信号通路，特别是PKC、PKA、Rho-Kinase和PI3- 激活剂。了解导致终末器官损伤发生的分子变化 疾病状态对于创建其他临床干预措施至关重要，这些干预措施可以与 传统疗法。

PROJECT SUMMARY (See instructions): One signaling pathway which data suggests may be involved in the adverse consequences of diabetes and hypertension is the JAK/STAT pathway. Our data support the idea that activation of this pathway is critical to the ability of ANGII to cause h3T)ertension in the models of ANG Il-high salt and high dose ANG II (normal salt). Preliminary data further suggest JAK2 appears to play a critical role in the molecular mechanisms utilized by ANG II to cause vascular contraction. These studies suggest that an alteration in the inhibitor of JAK2 activity, SHP-1, may be involved in the activation of JAK2 observed. Furthermore, in vivo, Norepinephrine also activates JAK2 during hypertension suggesting that JAK2 may be a common agent for the increase in blood pressure. Therefore, we propose to test the hypothesis that activation of the JAK/STAT pathway in vivo during hypertension contributes to the development of vascular endothelial dysfunction and renal complications as assessed by alterations in glomerular filtrate rate (GFR), renal blood flow and the development of glomerular sclerosis. The goal of these proposed studies is to use an integrative approach combining whole animal physiology with a biochemical analysis of the intracellular signaling mechanisms to elucidate the molecular mechanisms involved in the development of complications. To achieve this goal we are proposing three specific aims. Specific Aim 1: Determine if the same members of the JAK/STAT pathway are activated in the DOCA-salt, ANG Il-high salt and NE-lnfiised models of hypertension. Specific Aim 2: Determine the effects of hypertension on the role of the cytosolic protein tyrosine phosphatases, SHP-1, SHP-2 and PTP-IB, and suppressors of c3rtokine signaling (SOCS) that regulate the JAK/STAT pathway. Specific Aim 3: Determine the interaction of the JAK/STAT with other signaling pathways already implicated in hypertension, specifically PKC, PKA, Rho-kinase and PI3- kinase. Understanding the molecular changes that contribute to the development of end-organ damage in disease states is critical to create additional clinical interventions that could be used in conjunction wnth traditional therapy.