TNF-alpha: an immunologic precipitant of collapsing glomerulopathy

TNF-α：塌陷性肾小球病的免疫促发剂

基本信息

批准号：
7472565
负责人：
PETER JACOB NELSON
金额：
$ 8.28万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7472565
关键词：
Anti-Inflammatory Agents Anti-inflammatory Apoptotic Atrophic Award Blood capillaries Cells Clinical Cyclin-Dependent Kinases Cyclins Dendritic Cells Development Disease Epithelial Epithelial Cells Epithelium Fibrosis Funding Future G1 Phase Generations Glycogen Synthase Kinase 3 Human Hyperplasia ITGAX gene Immune Immune response Immunologics In Vitro Inflammatory Injury Interleukin-10 Kidney Knowledge Legal patent Lesion Lymphoid Maintenance Maps Mitogens Modeling Mus Necrosis Nephrons Outcome Parietal Pathogenesis Pathway interactions Pattern Pharmaceutical Preparations Principal Investigator Proliferating Property Publications Reagent Recruitment Activity Research Resistance Role Seminal Source Structure System TNF gene Therapeutic Tumor Necrosis Factor Receptor Tumor Necrosis Factor-alpha base capillary cell type cytokine glomerular filtration human TNF protein in vivo inhibitor/antagonist injured monolayer novel podocyte programs repaired response

项目摘要

DESCRIPTION (provided by applicant): Collapsing glomerulopathy (CG), a clinically aggressive and therapeutically resistant proliferative podocytopathy, develops predominantly in T helper type 1 (Th1)-polarizing disorders. Despite this strong clinical correlate in CG and knowledge of the pathogenic role of Th1 responses in other proliferative parenchymal renal lesions, little research has been done to determine whether Th1 effectors may precipitate or exacerbate CG. Based on leading results generated by us and others during the first two years of research under K08 DK065498 which suggest an important, targetable contribution from the pleotropic Th1 effector molecule, tumor necrosis factor-alpha (TNF-(), to the proliferative parenchymal injury in CG, this associated R03 proposal will undertake three new specific aims. In Specific Aim 1, we will determine whether soluble TNF-( is a mitogen for mouse and human glomerular visceral epithelial cells by engaging TNF receptors and inducing the expression of G1-phase cyclins. TNF-( is now known to directly promote the proliferation of several different epithelial cell-types in vitro and in vivo; however, the phenotypic response of glomerular visceral epithelial cells to soluble TNF-( is poorly understood. In Specific Aim 2, we will develop a manipulatable murine system to determine if the renal CD11c+ dendritic cell network serves as a dominant source of intra-renal TNF-( that may challenge glomeruli in CG. This system will also allow us to study the potential role of the renal dendritic cell network in other aspects of the pathogenesis of CG. In Specific Aim 3, we will determine whether second generation pharmacologic cyclin-dependent kinase / glycogen synthase kinase 3 (CDK/GSK-3) inhibitors, novel drugs for the treatment of CG, suppress TNF-( expression and induce IL-10 expression in activated renal CD11c+ dendritic cells. Inhibition of GSK-3 can determine whether pro- versus anti-inflammatory cytokines are produced by dendritic cells; we will determine if these drugs induce a similar phenotypic drug response from activated renal dendritic cells. These adjoining specific aims to K08 DK065498 will identify novel pathways whereby pro-inflammatory Th1 responses and, in particular, TNF-(, may contribute to the pathogenesis of CG and further our understanding of the integrative therapeutic properties of pharmacologic CDK/GSK-3 inhibitors. The outcomes from these specific aims will bolster the development of funding and research initiatives beyond K08 DK065498. The R03 award would also facilitate the publication of research-in-progress and provide ongoing support for technical assistance established during the first-half of K08 DK065498.

描述（由申请人提供）：塌陷性肾小球病 (CG) 是一种具有临床侵袭性和治疗耐药性的增殖性足细胞病，主要发生在 1 型辅助性 T (Th1) 极化疾病中。尽管 CG 与 Th1 反应在其他增殖性肾实质病变中的致病作用的知识有很强的临床相关性，但很少有研究来确定 Th1 效应物是否可能促进或加剧 CG。基于我们和其他人在 K08 DK065498 下的前两年研究中产生的主要结果，这些结果表明多效性 Th1 效应分子肿瘤坏死因子-α (TNF-()) 对增殖性实质损伤具有重要的、可靶向的贡献CG，相关的 R03 提案将实现三个新的具体目标，在具体目标 1 中，我们将确定可溶性 TNF-( 是否是小鼠和人类的有丝分裂原。肾小球内脏上皮细胞通过结合 TNF 受体并诱导 G1 期细胞周期蛋白的表达，目前已知可直接促进体外和体内几种不同上皮细胞类型的增殖；然而，肾小球内脏上皮细胞的表型反应。上皮细胞对可溶性 TNF-( 的影响尚不清楚。在具体目标 2 中，我们将开发一个可操作的小鼠系统来确定肾 CD11c+ 是否树突状细胞网络是肾内 TNF-( 的主要来源，可能会挑战 CG 中的肾小球。该系统还将使我们能够研究肾树突状细胞网络在 CG 发病机制其他方面的潜在作用。在具体目标 3 中，我们将确定第二代药理细胞周期蛋白依赖性激酶/糖原合成酶激酶 3 (CDK/GSK-3) 抑制剂（治疗 CG 的新药）是否能抑制 TNF-( 表达并诱导 IL-10 表达）激活的肾 CD11c+ 树突状细胞的抑制可以确定树突状细胞是否产生促炎细胞因子和抗炎细胞因子；我们将确定这些药物是否诱导类似的表型。 K08 DK065498 的这些相关具体目标将确定促炎性 Th1 反应（特别是 TNF-）的新途径，可能有助于 CG 的发病机制，并进一步加深我们对综合治疗特性的理解。这些特定目标的成果将促进 K08 DK065498 以外的资助和研究计划的发展。 R03 奖还将促进正在进行的研究的出版，并为 K08 DK065498 上半年建立的技术援助提供持续支持。