A new paradigm of glomerular immune cell homing

肾小球免疫细胞归巢的新范例

基本信息

批准号：
10608895
负责人：
JANOS PETI-PETERDI
金额：
$ 47.5万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-15 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10608895
关键词：
Affect Anatomy Anti-Inflammatory Agents Antibodies Antiinflammatory Effect Blood Vessels CD3 Antigens CD44 gene CD8-Positive T-Lymphocytes CD8B1 gene Cd68 Cell Culture Techniques Cell Separation Cell physiology Cells Cellular Infiltration Chemotaxis Complement Cytometry Development Diabetic Nephropathy Disease Extracellular Matrix FRAP1 gene Functional disorder Future Genes Genetic Glomerulonephritis Health Home Homing Immune In Vitro Inflammation Inflammatory Inflammatory Response Injury Kidney Kidney Diseases Knock-out Label Laboratories Leucocytic infiltrate Lupus Nephritis Macula densa Maintenance Microcirculation Modeling Molecular Mus PTPRC gene Pathway interactions Pattern Physiological Play Population Positioning Attribute Property Protein Biosynthesis Proteins Proteomics Role Serum Signaling Protein Streptozocin Stromal Cell-Derived Factor 1 Structure Testing Therapeutic Time Tissues Transgenic Mice Work cell growth cell type chemokine comorbidity cytokine density diabetic gain of function glomerular endothelium hemodynamics immunoregulation improved in vivo inhibitor kidney cell kidney cortex loss of function microscopic imaging migration mortality multiphoton microscopy nephrotoxicity non-diabetic novel therapeutic intervention optogenetics paracrine pre-clinical single-cell RNA sequencing systemic inflammatory response tool transcriptome transcriptomics translational therapeutics vascular bed

项目摘要

SUMMARY This study aims to investigate a radically new paradigm of glomerular immune cell homing and to uncover the underlying cell and molecular mechanisms and their role in physiological and renal inflammatory disease conditions including diabetic kidney disease (DKD) and lupus nephritis (LN). As an additional translational aim, these studies will inform the repurposing of current treatments for kidney disease and the development of new anti-inflammatory therapies. Circulating and kidney resident immune cells are known to preferentially home in and around the glomerulus compared to other vascular beds in both normal and inflammatory states, suggesting the presence of unique immunomodulatory mechanisms in the glomerular microcirculation that protect the kidney filter. However, the underlying cell and molecular mechanisms have been largely unknown. The focus of the proposed studies is a new function of the cells of the macula densa (MD) which are strategically positioned at the glomerular vascular entrance and traditionally known to regulate renal and glomerular hemodynamics. Our laboratory recently identified that MD cells have the highest rate of protein synthesis among all kidney cell types and they secrete a variety of paracrine-acting angiogenic, cell growth and patterning, and extracellular matrix signaling proteins. Preliminary work identified the high MD-enrichment of several pathways and genes in the inflammatory response and cellular infiltration by leukocytes (e.g., Cxcl12, Cxcl14, Ptgs2, Ptges, Anxa1, Ccn1, Mif) and observed the MD-centric glomerular density and migration of CD44+ and CD8+ T cells in inflammatory diseases including lupus nephritis. Our central hypothesis is that MD cells drive the preferential glomerular homing of immune cells by the release of paracrine-acting pro-inflammatory factors including chemokines and cytokines. This project will use comprehensive experimental approaches including new transgenic mice with conditional, inducible and optogenetic tools (MD-mTORgof/lof, MD-Ai27, MD-Ai39, CCN1-knockout (KO), CCN1- GFP mice), models of renal and systemic inflammation (NTS, STZ-DKD, NZM.2328 LN models), in vivo MPM imaging, MD transcriptome analysis, in vitro cell culture and proteomics, and pre-clinical therapeutic translation. The specific aims are to (1) Examine the global immunomodulatory role and mechanisms of MD cells under physiological and renal inflammatory disease conditions, (2) Elucidate the renal anti-inflammatory role of CCN1, and (3) Test the anti-inflammatory effects of SGLT2 inhibitors (SGLT2i). These newly identified MD mechanisms may be targeted and will inform the development of future anti-inflammatory therapeutic strategies.

概括本研究旨在研究肾小球免疫细胞归巢的全新范例并揭示潜在的细胞和分子机制及其在生理和肾脏炎症疾病中的作用疾病包括糖尿病肾病（DKD）和狼疮性肾炎（LN）。作为额外的翻译目标，这些研究将为当前肾脏疾病治疗方法的重新利用和新药物的开发提供信息抗炎治疗。已知循环和肾脏驻留免疫细胞优先驻留在以及肾小球周围与正常和炎症状态下的其他血管床相比，表明肾小球微循环中存在独特的免疫调节机制，可保护肾脏筛选。然而，潜在的细胞和分子机制在很大程度上尚不清楚。重点是拟议的研究是密集黄斑（MD）细胞的一项新功能，这些细胞战略性地位于肾小球血管入口，传统上已知可调节肾脏和肾小球血流动力学。我们的实验室最近发现，MD细胞在所有肾细胞类型中具有最高的蛋白质合成率它们分泌多种旁分泌作用的血管生成、细胞生长和模式以及细胞外基质信号蛋白。初步工作确定了多种途径和基因的高度 MD 富集。炎症反应和白细胞细胞浸润（例如 Cxcl12、Cxcl14、Ptgs2、Ptges、Anxa1、Ccn1、 Mif）并观察炎症中以 MD 为中心的肾小球密度和 CD44+ 和 CD8+ T 细胞的迁移包括狼疮性肾炎在内的疾病。我们的中心假设是 MD 细胞优先驱动肾小球通过释放旁分泌作用的促炎因子（包括趋化因子和细胞因子。该项目将使用综合实验方法，包括具有条件、诱导和光遗传学工具（MD-mTORgof/lof、MD-Ai27、MD-Ai39、CCN1-敲除 (KO)、CCN1- GFP 小鼠）、肾脏和全身炎症模型（NTS、STZ-DKD、NZM.2328 LN 模型）、体内 MPM 成像、MD 转录组分析、体外细胞培养和蛋白质组学以及临床前治疗翻译。具体目标是（1）研究MD细胞在免疫调节作用下的整体免疫调节作用和机制。生理和肾脏炎症疾病条件，（2）阐明CCN1的肾脏抗炎作用， (3)测试SGLT2抑制剂(SGLT2i)的抗炎作用。这些新发现的MD机制可能是有针对性的，并将为未来抗炎治疗策略的发展提供信息。