Cellular Mechanisms of Renal Interstitial Fibrosis

肾间质纤维化的细胞机制

基本信息

批准号：
8318861
负责人：
JEFFREY L BARNES
金额：
$ 27.46万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8318861
关键词：
1-Phosphatidylinositol 3-Kinase 4-ethoxymethylene-2-phenyl-2-oxazoline-5-one Angiotensin Receptor Antisense Oligonucleotides Attention Biochemical Biological Assay Blood Vessels Cell Proliferation Cell physiology Cells Chronic Kidney Failure Data Development Dialysis procedure Dominant-Negative Mutation Early treatment Event Family Fibroblasts Fibrosis Generations Gleevec Growth Factor Immunofluorescence Immunologic In Situ Hybridization In Vitro Injection of therapeutic agent Kidney Kidney Diseases Kidney Failure Kidney Transplantation Knockout Mice Label Lead Location MADH2 gene MAP Kinase Gene MAPK3 gene Mitogen-Activated Protein Kinase 3 Modeling Monomeric GTP-Binding Proteins Myofibroblast Oxidases PDGFRB gene Pathway interactions Phosphorylation Platelet-Derived Growth Factor Protein Isoforms Reactive Oxygen Species Receptor Activation Receptor Signaling Regulation Relative (related person)Research Role Signal Pathway Signal Transduction Signaling Protein Staging Structure Transforming Growth Factor beta Receptors Tubular formation Vascular Diseases acetovanillone autocrine cell motility cell type design glomerulosclerosis in vivo inhibitor/antagonist insight intercellular communication interstitial migration public health relevance receptor research study rho

项目摘要

DESCRIPTION (provided by applicant): Progression of renal disease leads to common consequences including interstitial fibrosis, glomerulosclerosis, vascular narrowing, and renal failure, ultimately requiring dialysis or renal transplantation. The kidney myofibroblast is the cell type most responsible for matrix accumulation during renal fibrosis. Although there is a large amount of data on mechanisms of interstitial myofibroblast matrix synthesis late in the course of renal fibrosis, information on the earliest cellular events involving myofibroblast encroachment into the perivascular and interstitial spaces prior to matrix accumulation is lacking. Experiments are proposed to examine mechanisms of myofibroblast encroachment (migration and proliferation) in a model of accelerated renal fibrosis in which myofibroblasts first originate from perivascular and periglomerular regions. Our central hypothesis is: Activation of PDGFR-2 and TGF-beta receptor induces fibroblast migration and proliferation into the peritubular interstitium via Rho/ROCK modulated ROS generation and transduction of PI3-kinase/Akt, MAPK (ERK1/2) signaling pathways early during the progression of renal fibrosis. The following aims are set: Aim 1. NAD(P)H oxidase-derived ROS are involved in myofibroblast interstitial encroachment early during the course of kidney fibrosis; Aim 2. ROS-induced interstitial myofibroblast migration, proliferation and matrix synthesis is a consequence of PDGFR-2 and TGF- beta receptor activation; Aim 3. ROS generation through PDGFR-2 and TGF-2 receptor regulate SMAD2/3, Rho/ROCK, ERK1/2 and Akt signaling cascades, initiating interstitial myofibroblast migration, proliferation, and matrix synthesis. PDGF BB and TGF2-1 initiate ROS generation in vascular disease. Experiments are designed to critically examine a role for NAP(P)H oxidase and associated phox subunits in ROS generation, PDGFR-2 and TGF-2 receptor activation and signaling pathways on myofibroblast migration, proliferation and matrix synthesis in vitro and in vivo. Specifically, a role for the NAD(P)H oxidase pathway (Nox2 and Nox4 and phox subunits) will be examined in PDGFR-2 and TGF-2 receptor transduction of SMADs, Rho/ROCK, PI3K, and ERK1/2 regulation of activation of kidney myofibroblast. These studies will provide much needed insight on mechanisms of myofibroblast activation during the early stages of renal fibrosis. PUBLIC HEALTH RELEVANCE: To date, the majority of research on renal interstitial fibrosis has focused on late changes associated with matrix accumulation, with little attention on early events of myofibroblast encroachment (migration and proliferation) into the interstitium. Understanding the mechanisms of myofibroblast encroachment before fibrosis occurs could lead to new therapies in the early treatment of chronic renal disease. This application focuses on a role for reactive oxygen species (ROS) in renal myofibroblast encroachment early during the initial stages of fibrosis.

描述（由申请人提供）：肾脏疾病的进展会导致共同的后果，包括间质纤维化，肾小球硬化，血管变窄和肾衰竭，最终需要透析或肾移植。肾脏肌纤维细胞是肾纤维化过程中基质积累最大的细胞类型。尽管在肾纤维化过程的后期，有大量有关间质肌纤维细胞基质合成机制的数据，但缺乏涉及肌纤维细胞侵占到血管周围和间质空间的最早细胞事件的信息。提出了实验来检查在加速肾纤维化模型中，肌纤维细胞侵占（迁移和增殖）的机制，在该模型中，肌纤维细胞首先起源于周血管周围和周围环形区域。我们的中心假设是：PDGFR-2和TGF-BETA受体的激活诱导成纤维细胞的迁移，并通过Rho/Rock调制ROS的产生和PI3-激酶/AKT的转导MAPK，MAPK（ERK1/2）在肾纤维纤维纤维进展过程中的早期信号通路。设定了以下目标：目标1。NAD（P）H氧化酶衍生的ROS在肾纤维化过程中早期参与肌纤维细胞间质侵占； AIM2。ROS诱导的间质肌纤维细胞迁移，增殖和基质合成是PDGFR-2和TGF-β受体激活的结果。 AIM 3。通过PDGFR-2和TGF-2受体产生ROS，调节SMAD2/3，RHO/ROCK，ERK1/2和AKT信号级联，启动间质肌纤维细胞迁移，增殖和基质合成。 PDGF BB和TGF2-1在血管疾病中引发ROS产生。设计实验旨在批判性地检查ROS生成，PDGFR-2和TGF-2受体激活中NAP（P）H氧化酶以及相关的PHOX亚基的作用，以及在体外和VIVO中的肌纤维细胞迁移，增殖和基质合成中的作用。具体而言，将检查NAD（P）H氧化酶途径（NOX2和NOX4和PHOX亚基）的作用，将在SMADS，RHO/ROCK，PI3K和ERK1/2的PDGFR-2和TGF-2受体转导中进行检查。这些研究将为肾纤维化的早期阶段中肌纤维细胞激活的机制提供急需的见解。公共卫生相关性：迄今为止，大多数关于肾脏间质纤维化的研究集中在与基质积累相关的后期变化上，而对肌纤维细胞侵占（迁移和增殖）的早期事件的关注很少。在发生纤维化之前，了解肌纤维细胞侵占的机制可能会导致早期治疗慢性肾脏疾病的新疗法。该应用集中在纤维化初始阶段的早期肾脏成肌纤维细胞侵占中的活性氧（ROS）的作用。