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

项目总结（见说明）： 数据显示，一种信号通路可能与糖尿病的不良后果有关， 高血压是JAK/STAT通路。我们的数据支持这一观点，即激活这一途径对 在ANG Ⅱ-高盐和高剂量ANG Ⅱ（正常盐）模型中ANG Ⅱ引起h3 T）升高的能力。 初步数据进一步表明，JAK 2似乎在细胞凋亡所利用的分子机制中发挥关键作用。 ANG II引起血管收缩。这些研究表明，JAK 2活性抑制剂的改变， SHP-1可能参与JAK 2的激活。此外，在体内，去甲肾上腺素也激活 JAK 2在高血压中的表达表明JAK 2可能是血压升高的常见因素。 因此，我们建议测试JAK/STAT通路在体内激活的假设， 高血压有助于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）、肾血流量和肾小球滤过率（GFR）的变化来评估。 硬化症这些拟议研究的目标是使用一种综合方法， 生理学与细胞内信号传导机制的生化分析，以阐明分子 参与并发症发展的机制。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JAK/STAT通路的相同成员是否在DOCA盐中被激活， ANG II-高盐和NE-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c3受体抑制因子的作用 信号传导（SOCS），调节JAK/STAT通路。具体目标3：确定JAK/STAT的相互作用 与其他已经参与高血压的信号通路，特别是PKC，PKA，Rho激酶和PI 3- 激酶。了解导致终末器官损伤的分子变化， 疾病状态对于创建可与疾病状态结合使用的额外临床干预至关重要。 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.