权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Cellular and Molecular Mechanisms of Renal Anemia

肾性贫血的细胞和分子机制

基本信息

批准号：
9275414
负责人：
Volker Hans Haase
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
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/9275414
关键词：
Address Alleles Anemia Applications Grants Biology Blood Cardiovascular system Cell Compartmentation Cell Lineage Cells Cellular biology Characteristics Chronic Kidney Failure Complex Consumption Development Dialysis procedure Dioxygenases EPO gene End stage renal failure Erythrocytes Erythropoiesis Erythropoietin Future Gene Expression Regulation Gene Targeting Genes Genetic Genetic Transcription Genetically Engineered Mouse Glycoproteins Goals Grant Homeostasis Hormones Hypoxia Hypoxia Inducible Factor Hypoxia-Inducible Factor Pathway Imaging technology Impairment In Vitro Injury Kidney Kidney Diseases Kidney Failure Laboratories Link Measurement Modeling Molecular Molecular Profiling Morbidity - disease rate Nephrology Oxygen Pathogenesis Pathway interactions Patient Care Patients Pharmacology Physiological Plasticizers Population Procollagen-Proline Dioxygenase Production Recombinant Erythropoietin Regulation Regulator Genes Regulatory Element Renal Interstitial Cell 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 public health relevance response tool transcription factor transcriptome

项目摘要

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）：