Role of COX2 in Medullary Interstitial Cell Survival and Function

COX2 在髓质间质细胞存活和功能中的作用

• 批准号: 7728127
• 负责人: GILBERT WOLFRAM MOECKEL
• 金额: $ 5.85万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7728127
• 关键词: Address; Apoptosis; Apoptotic; Blood Pressure; Blood flow; Cell Death; Cell Survival; Cell physiology; Cells; Condition; Coxibs; Data; Dominant-Negative Mutation; Duct (organ) structure; E protein; Edema; Eicosanoids; Excretory function; FYN gene; Goals; Health; High Blood Pressure; Hypertension; Hypotension; Impairment; In Vitro; Induction of Apoptosis; Injury; Kidney; Lead; Limb structure; MAP Kinase Gene; Maintenance; Mediating; Membrane Potentials; Mitochondria; Morbidity - disease rate; Myocardial Infarction; Null Lymphocytes; PTGS2 gene; Pharmaceutical Preparations; Process; Production; Prostaglandins; Prostaglandins E; Protein Overexpression; Public Health; Regulation; Role; Signal Pathway; Signal Transduction; Site; Societies; Stress; Stroke; Testing; Therapeutic; Thick; Time; Vasopressins; absorption; base; blood pressure regulation; cyclooxygenase 2; design; in vivo; insight; interstitial cell; kidney cell; kidney medulla; mitochondrial membrane; mortality; paracrine; prevent; prostaglandin EP3 receptor; src-Family Kinases

DESCRIPTION (provided by applicant): Hypertension is an important public health problem and one of the major causes of morbidity and mortality in all western societies. Several studies have emphasized the importance of the renal medullary blood flow in long term regulation of blood pressure. Medullary blood flow is regulated by eicosanoids such as prostaglandins, which are produced in the medulla and act locally. The medullary interstitial cell (MIC) is the predominant site of medullary prostanoid production. Prostanoid-dependent cell survival mechanisms, such as organic osmolyte accumulation, protect cells in the renal medulla against hyperosmotic stress. We hypothesize that impairment of prostanoid-dependent MIC survival leads to decrease in medullary blood flow and rise in arterial blood pressure. Our hypothesis is based on our exciting in vivo and in vitro data that show that inhibition of renal prostaglandin synthesis leads to both impairment of medullary interstitial cell survival and medullary blood flow. However, the exact mechanisms how prostanoids mediate osmolyte accumulation and how these ameliorate hypertonic stress-induced injury to medullary interstitial cells is unknown. We will test our hypothesis by examining the mechanisms that lead to hypertonicity-induced cell death, and how osmolyte prevent mitochondrial injury under hyperosmotic conditions, (specific aim 1). We will then progress to investigate the role of Src family kinases (SFKs) on hypertonicity-induced signaling that mediates increased prostanoid synthesis (COX2) and osmolyte accumulation (TonEBP/NFAT5) (specific aim 2). Finally, we will examine the role of the prostaglandin E protein receptor (EP3), which is highly prevalent in the medulla, on osmolyte transport regulation and cell survival in vivo and in vitro (specific aim 3). The mechanisms that regulate medullary blood flow and the role of the medullary interstitial cell in long term blood pressure regulation are poorly understood. The studies in this proposal address this major gap in our understanding. Our long term goals are to gain insight into the mechanistic process that leads to the important health problem of hypertension. It is necessary to understand these processes in order to design effective therapeutic approaches and develop new drugs to treat hypertension. High blood pressure is a common health problem and a major cause of heart attack and stroke in western societies. Several studies have shown the importance of good blood flow to the kidney for the maintenance of low blood pressure. Certain kidney cells are super-regulators of blood flow and their survival is highly important to keep blood pressure low. The goals of this study are to understand better how these super-regulator cells survive and keep blood pressure low. It is necessary to understand how these cells function in order to design better drugs to treat high blood pressure.

描述(由申请人提供)： 高血压是一个重要的公共卫生问题，也是所有西方社会发病率和死亡率的主要原因之一。一些研究强调了肾髓质血流在血压长期调节中的重要性。髓质的血流量由前列腺素等二十烷基类物质调节，这些物质在髓质中产生并在局部起作用。髓质间质细胞(MIC)是产生类前列腺素的主要部位。依赖前列腺素的细胞生存机制，如有机渗透压积聚，保护肾髓质细胞免受高渗应激。我们假设前列腺素依赖的MIC存活受损会导致延髓血流量减少和动脉血压升高。我们的假设是基于我们令人兴奋的体内和体外数据，这些数据表明，抑制肾脏前列腺素合成会导致髓质间质细胞存活和髓质血流量的损害。然而，前列腺素如何介导渗透压蓄积以及如何改善高渗应激引起的骨髓间质细胞损伤的确切机制尚不清楚。我们将通过研究导致高渗诱导细胞死亡的机制，以及渗透激素如何在高渗透条件下防止线粒体损伤来检验我们的假设(特定目标1)。然后，我们将继续研究Src家族激酶(SFK)在高张诱导的信号转导中的作用，该信号介导前列腺素合成增加(COX2)和渗透压积聚(TONEBP/NFAT5)(特定目标2)。最后，我们将研究在延髓中广泛存在的前列腺素E蛋白受体(EP3)在体内和体外渗透调节和细胞存活中的作用(特定目标3)。调节髓质血流的机制和髓间质细胞在长期血压调节中的作用还知之甚少。这项建议中的研究解决了我们理解中的这一重大差距。我们的长期目标是深入了解导致高血压这一重要健康问题的机制过程。为了设计有效的治疗方法和开发治疗高血压的新药，有必要了解这些过程。在西方社会，高血压是一个常见的健康问题，也是心脏病发作和中风的主要原因。多项研究表明，良好的肾脏血流对于维持低血压非常重要。某些肾脏细胞是血液流动的超级调节器，它们的存活对保持低血压非常重要。这项研究的目标是更好地了解这些超级调节细胞是如何存活并保持低血压的。为了设计更好的治疗高血压的药物，有必要了解这些细胞是如何发挥作用的。