Modulators of Kidney Fibrosis

肾脏纤维化调节剂

基本信息

批准号：
7991690
负责人：
Detlef Olaf Schlondorff
金额：
$ 7.93万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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：
2010-01-07 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7991690
关键词：
A Mouse Adoptive Transfer Adriamycin PFS Atrophic Biopsy Blood capillaries Bone Marrow CCR1 gene CCR5 gene CXCR4 gene Cells Chronic Collagen Data Disease Disease Outcome Disease Pathway End stage renal failure Epithelial Cells Fibrosis Future Generations Homing Hypoxia In Vitro Infiltration Injury Kidney Kidney Diseases Kidney Failure Knock-out Knockout Mice Laboratories Lesion Leukocytes Ligands Mediator of activation protein Membranous Glomerulonephritis Mind Modeling Molecular Molecular Profiling Mus Myeloid Cells Nephrosis Outcome Patients Pattern Phenotype Population Process Protein Isoforms Public Health Publishing Receptor Activation Regulation Renal glomerular disease Role Secondary to Site System TLR2 gene Testing Tissues Toll-like receptors Translating Tubular formation Work biglycan capillary chemokine chemokine receptor cytokine design human disease hypoxia inducible factor 1 in vivo in vivo Model interstitial macrophage monocyte novel public health relevance receptor receptor expression research study sensor therapy design

项目摘要

DESCRIPTION (provided by applicant): The problem of progression of renal fibrosis leading to endstage renal failure remains unresolved. The progressive tubulointerstitial lesions are characterized by tubuloepithelial damage and atrophy, peritubular capillary rarefication and interstitial fibrosis with leukocyte infiltrates. Work from the PI's has provided evidence that the leukocyte infiltrate is chemokine dependent and contributes to the progressive fibrosis. The present proposal will focus on factors contributing to the generation of chemokines and cytokines at the site of injury and to the resulting leukocyte infiltration and fibrosis. We will examine the hypothesis: Hypoxia and the generation of Damage Associated Molecular Pattern (DAMP) molecules occur at sites of chronic tubulointerstitial damage. Hypoxia will activate HIF transscription factors and DAMP molecules will activate Toll-like receptors(TLR) both on epithelial cells and on residentmonocyte/macrophages(M/M). HIF and TLR activation will generate cytokines and chemokines which will in turn determine the specific type of infiltrating bone marrow (b.m.) derived cells. Together with direct local activation of M/M by HIF and TLRs, the infilux of b.m. derived cells will determine the further outcome of the disease process. The specific aims are to identify the contribution of epithelial cells and of b.m. derived cells activated by hypoxia via HIF and by DAMP molecules via TLRs to the outcome of tubulointerstitial fibrosis secondary to glomerular disease. This will be achieved by a combination of in vitro and in vivo as well as ex vivo-in vivo experiments using conditional knockouts for two HIF isoforms, HIF-11 and 21, as well as knockouts for TLR2 and 4. The in vivo models to be used are adriamycin nephrosis and collagen 4A3 deficient -Alport mice. Both models develop secondary interstitial disease with leukocyte infiltration and fibrosis. We will also attempt to identify the specific chemokine receptors involved in the recruitment of specific subsets of myeloid cells to the tubulointerstitial lesions developing in these models by using chemokine deficient myeloid cells. The combination of these experiments should provide us with important and novel information on the role of HIF and TLRs as sensors for chronic renal injury and that of chemokine chemokine receptors as effectors for the infiltration of specific populations of b.m.derived cells in the process of progressive interstitial fibrosis. The concept of hypoxia generating DAMP molecules, which inturn act as intrinsic TLR activators may open up a totally new perspective on mechanisms of progression of renal diseases. Obviously this information is prerequsite for designing future strategies to interfere with progressive renal fibrosis. PUBLIC HEALTH RELEVANCE End stage renal disease is a major public health problem with insufficient therapies at present. We plan to identify new disease pathways that will allow the design of novel therapies.

描述（由申请人提供）：导致末期肾衰竭的肾纤维化进展问题仍未解决。进行性微管间质病变的特征是微管上皮损伤和萎缩，周围毛细血管稀疏性和白细胞浸润的间质纤维化。 PI的工作提供了证据表明白细胞浸润是趋化因子依赖性的，并有助于进行性纤维化。本提案将集中于损伤部位以及由此产生的白细胞浸润和纤维化的因素。我们将研究以下假设：缺氧和损伤的产生相关的分子模式（潮湿）分子发生在慢性微管间损伤部位。缺氧将激活HIF的反映因子，并且潮湿的分子将激活上皮细胞和常生物细胞/巨噬细胞（M/M）上的Toll样受体（TLR）。 HIF和TLR激活将产生细胞因子和趋化因子，进而确定浸润骨髓（B.M.）衍生细胞的特定类型。与HIF和TLR对M/M的直接局部激活一起，B.M.的Infilux衍生细胞将决定疾病过程的进一步结果。具体目的是确定上皮细胞和B.M.的贡献。通过HIF和通过TLRS潮湿的分子激活的细胞衍生细胞，以肾小球疾病继发于肾小管间质纤维化的结果。这将通过使用有条件的HIF同工型HIF-11和21的有条件敲除以及TLR2和4的敲除。用于使用的INPRAIMCIN肾脏病和胶原蛋白4AA3 3A33防御-Al-Alport-Ports-Ports-Ports-Alport-Ports-Ports-Alport-Ports-Alport-Ports Mials鼠标。两种模型都会出现伴有白细胞浸润和纤维化的次生疾病。我们还将尝试通过使用趋化因子缺乏的髓样细胞来识别粒细胞特定子集募集到在这些模型中开发的肾小管间质病变中涉及的特定趋化因子受体。这些实验的结合应为我们提供有关HIF和TLR作为慢性肾损伤的传感器和趋化因子趋化因子受体的传感器的作用的重要和新颖信息，作为在进行性间质纤维化过程中B.M.衍生细胞特定群体浸润的效应子。产生潮湿分子的低氧概念，即内在的TLR激活剂可能会为肾脏疾病进展的机制提供全新的观点。显然，这些信息是设计未来策略以干扰进行性肾纤维化的预先矿石。公共卫生相关性目前疗法不足，末期肾脏疾病是一个主要的公共卫生问题。我们计划确定将允许设计新疗法的新疾病途径。