Cellular and Molecular Mechanisms of Renal Anemia

肾性贫血的细胞和分子机制

• 批准号: 8966671
• 负责人: Volker Hans Haase
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-10-01 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8966671
• 关键词: Address; Alleles; Anemia; Applications Grants; Biology; Blood; Boxing; Cardiovascular system; Cell Lineage; Cells; Cellular biology; Characteristics; Chronic Kidney Failure; Complex; Consumption; Development; Dialysis procedure; Dioxygenases; End stage renal failure; Erythrocytes; Erythropoiesis; Erythropoietin; Future; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetically Engineered Mouse; Glycoproteins; Goals; Grant; Health; Homeostasis; Hormones; Hypoxia; Hypoxia Inducible Factor; Hypoxia-Inducible Factor Pathway; Imaging technology; Impairment; In Vitro; Injury; Kidney; Kidney Failure; Laboratories; Link; Measurement; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Nephrology; Oxygen; Pathogenesis; Pathway interactions; Patient Care; Patients; Physiological; Population; Procollagen-Proline Dioxygenase; Production; Recombinant Erythropoietin; Regulation; Regulator Genes; Regulatory Element; Renal Interstitial Cell; Renal function; Renin; Resolution; Role; Safety; Site; Stress; Supportive care; Techniques; Transactivation; Ureteral obstruction; Veterans; Work; bHLH-PAS factor HLF; cell type; cost; genetic manipulation; genome-wide; improved; in vivo; injured; insight; interstitial; interstitial cell; kidney cell; liver hypoxia; mRNA Expression; mortality; novel; novel therapeutics; response; tool; transcription factor; transcriptome

DESCRIPTION (provided by applicant): Our long-term goal is to understand the pathogenesis of renal anemia and to develop new and safe therapies for its treatment. Anemia is a classic manifestation of advanced chronic kidney disease (CKD) and results from the diminished ability of the diseased kidney to produce adequate amounts of erythropoietin (EPO), the glycoprotein hormone that is essential for red blood production. Anemia associated with CKD or end stage renal disease (ESRD) is typically treated with recombinant EPO. The use of recombinant EPO not only represents a major cost factor in the care of patients with advanced CKD and ESRD, but also has raised significant cardiovascular safety concerns, which prompted the FDA to issue several black box warnings. While the administration of recombinant EPO to renal patients has been a hallmark of supportive care in Nephrology for more than 20 years, the molecular mechanisms that underlie the pathogenesis of renal anemia are surprisingly poorly understood. A key pathway in the regulation of renal EPO production is the hypoxia-inducible factor (HIF) pathway. Although the hypoxic induction of EPO serves as a paradigm for hypoxic gene regulation, the regulation of renal EPO synthesis under renal injury conditions is incompletely understood on both, the cellular and the molecular level. Over the last 5 years our laboratory and other groups have demonstrated that HIF-2 regulates the hypoxic induction of EPO in the kidney and liver, and that the HIF pathway can be pharmacologically targeted to treat patients with anemia. To understand the regulation of renal EPO production on a cellular and molecular level we have begun to use genetic and pharmacologic approaches to dissect the HIF/EPO axis in normal and in injured kidneys. Under this grant, we hypothesize that HIF-2 controls renal EPO production by regulating renal interstitial cell plasticity. We use genetically engineered mice to a) define the cell types in the kidney that have EPO-producing ability, b) to determine their contribution in the regulation of erythropoiesis at baseline and under hypoxic stress conditions, c) to characterize the role of the three major HIF prolyl-hydroxylases in the regulation of renal interstitial hypoxia responses and d) to examine HIF-2 function under renal injury conditions.

描述（由申请人提供）： 我们的长期目标是了解肾性贫血的发病机制，并开发新的、安全的治疗方法。贫血是晚期慢性肾病 (CKD) 的典型表现，是由于患病肾脏产生足够量的促红细胞生成素 (EPO) 的能力下降所致，促红细胞生成素是红细胞生成所必需的糖蛋白激素。与 CKD 或终末期肾病 (ESRD) 相关的贫血通常用重组 EPO 治疗。重组 EPO 的使用不仅是治疗晚期 CKD 和 ESRD 患者的主要成本因素，而且还引起了重大的心血管安全问题，促使 FDA 发布了几项黑框警告。尽管 20 多年来，对肾脏患者施用重组 EPO 一直是肾脏病学支持治疗的标志，但令人惊讶的是，人们对肾性贫血发病机制的分子机制却知之甚少。调节肾脏 EPO 产生的关键途径是缺氧诱导因子 (HIF) 途径。尽管EPO的缺氧诱导是缺氧基因调节的范例，但肾损伤条件下肾EPO合成的调节在细胞和分子水平上尚不完全清楚。在过去的 5 年里，我们的实验室和其他小组已经证明，HIF-2 调节肾脏和肝脏中 EPO 的缺氧诱导，并且 HIF 途径可以在药理学上靶向治疗贫血患者。为了在细胞和分子水平上了解肾脏 EPO 产生的调节，我们已经开始使用遗传和药理学方法来剖析正常和受损肾脏中的 HIF/EPO 轴。根据这项资助，我们假设 HIF-2 通过调节肾间质细胞的可塑性来控制肾 EPO 的产生。我们使用基因工程小鼠 a) 定义肾脏中具有 EPO 生成能力的细胞类型，b) 确定它们在 基线和缺氧应激条件下红细胞生成的调节，c) 表征三种主要 HIF 脯氨酰羟化酶在肾间质缺氧调节中的作用 反应和 d) 检查肾损伤条件下的 HIF-2 功能。