Modulators of Kidney Fibrosis

肾脏纤维化调节剂

基本信息

批准号：
7924721
负责人：
Detlef Olaf Schlondorff
金额：
$ 35.39万
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：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7924721
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）：肾纤维化进展导致终末期肾衰竭的问题仍未解决。进行性肾小管间质病变的特点是肾小管上皮损伤和萎缩、肾小管周围毛细血管稀疏和间质纤维化伴白细胞浸润。 PI 的工作提供了证据，表明白细胞浸润具有趋化因子依赖性，并导致进行性纤维化。目前的提案将重点关注导致损伤部位趋化因子和细胞因子产生以及由此导致的白细胞浸润和纤维化的因素。我们将检验以下假设：缺氧和损伤相关分子模式 (DAMP) 分子的产生发生在慢性肾小管间质损伤部位。缺氧会激活 HIF 转录因子，DAMP 分子会激活上皮细胞和常驻单核细胞/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，进而决定浸润骨髓 (b.m.) 衍生细胞的具体类型。加上 HIF 和 TLR 对 M/M 的直接局部激活，b.m 的流入。衍生细胞将决定疾病过程的进一步结果。具体目标是确定上皮细胞和骨髓的贡献。缺氧通过 HIF 激活衍生细胞，并通过 TLR 被 DAMP 分子激活，导致继发于肾小球疾病的肾小管间质纤维化。这将通过结合体外和体内以及离体-体内实验来实现，使用两种 HIF 异构体 HIF-11 和 21 的条件敲除，以及 TLR2 和 4 的敲除。使用的是阿霉素肾病和胶原蛋白4A3缺陷-Alport小鼠。两种模型都会出现继发性间质性疾病，伴有白细胞浸润和纤维化。我们还将尝试通过使用趋化因子缺陷的骨髓细胞来鉴定参与将特定的骨髓细胞亚群募集到这些模型中形成的肾小管间质病变中的特定趋化因子受体。这些实验的结合应该为我们提供关于 HIF 和 TLR 作为慢性肾损伤传感器的作用以及趋化因子受体作为进行性间质性细胞浸润过程中特定骨髓来源细胞群浸润效应器的作用的重要而新颖的信息。纤维化。缺氧产生 DAMP 分子（反过来又充当内在 TLR 激活剂）的概念可能为肾脏疾病进展机制开辟全新的视角。显然，这些信息是设计未来干预进行性肾纤维化策略的先决条件。公共卫生相关性终末期肾病是一个重大的公共卫生问题，目前治疗方法不足。我们计划确定新的疾病途径，从而设计新的疗法。