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:
- 金额:$ 47.5万
- 依托单位:
- 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:
- 关键词:AffectAnatomyAnti-Inflammatory AgentsAntibodiesAntiinflammatory EffectBlood VesselsCD3 AntigensCD44 geneCD8-Positive T-LymphocytesCD8B1 geneCd68Cell Culture TechniquesCell SeparationCell physiologyCellsCellular InfiltrationChemotaxisComplementCytometryDevelopmentDiabetic NephropathyDiseaseExtracellular MatrixFRAP1 geneFunctional disorderFutureGenesGeneticGlomerulonephritisHealthHomeHomingImmuneIn VitroInflammationInflammatoryInflammatory ResponseInjuryKidneyKidney DiseasesKnock-outLabelLaboratoriesLeucocytic infiltrateLupus NephritisMacula densaMaintenanceMicrocirculationModelingMolecularMusPTPRC genePathway interactionsPatternPhysiologicalPlayPopulationPositioning AttributePropertyProtein BiosynthesisProteinsProteomicsRoleSerumSignaling ProteinStreptozocinStromal Cell-Derived Factor 1StructureTestingTherapeuticTimeTissuesTransgenic MiceWorkcell growthcell typechemokinecomorbiditycytokinedensitydiabeticgain of functionglomerular endotheliumhemodynamicsimmunoregulationimprovedin vivoinhibitorkidney cellkidney cortexloss of functionmicroscopic imagingmigrationmortalitymultiphoton microscopynephrotoxicitynon-diabeticnovel therapeutic interventionoptogeneticsparacrinepre-clinicalsingle-cell RNA sequencingsystemic inflammatory responsetooltranscriptometranscriptomicstranslational therapeuticsvascular 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.
摘要
这项研究旨在探索一种全新的肾小球免疫细胞归巢范式,并揭示
生理性和肾炎性疾病的细胞和分子机制及其作用
疾病包括糖尿病肾病(DKD)和狼疮性肾炎(LN)。作为一个额外的翻译目标,
这些研究将为肾脏疾病的当前治疗方法的重新定位和新的
消炎疗法。已知循环和肾脏常驻免疫细胞优先归巢于
以及肾小球周围与其他血管床在正常和炎症状态下的比较,提示
肾小球微循环中存在保护肾脏的独特免疫调节机制
过滤。然而,其潜在的细胞和分子机制在很大程度上是未知的。这次会议的重点是
拟议的研究是致密黄斑(MD)细胞的一项新功能,该细胞位于
肾小球的血管入口,传统上被认为调节肾脏和肾小球的血流动力学。我们的
实验室最近发现,在所有类型的肾脏细胞中,MD细胞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、细胞生长和构图以及细胞外基质。
信号蛋白。初步工作确定了几个途径和基因的高度MD-浓缩
白细胞(如CxCL12、CxCl14、Ptgs2、Ptges、Anxa1、Ccn1、
MIF),观察炎症过程中以MD为中心的肾小球密度和CD44+、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细胞驱动优先肾小球
免疫细胞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。该项目将使用全面的实验方法,包括新的转基因小鼠
条件性、诱导性和光遗传工具(MD-mTORgOF/10F、MD-Ai27、MD-Ai39、CCN1-基因敲除(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。
其具体目的是:(1)研究MD细胞在全球的免疫调节作用和机制。
生理和肾脏炎症状态,(2)阐明CCN1的肾脏抗炎作用,
(3)检测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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JANOS PETI-PETERDI其他文献
JANOS PETI-PETERDI的其他文献
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{{ truncateString('JANOS PETI-PETERDI', 18)}}的其他基金
Novel regulatory mechanisms of the glomerular endothelium
肾小球内皮的新调节机制
- 批准号:
10006881 - 财政年份:2019
- 资助金额:
$ 47.5万 - 项目类别:
Novel regulatory mechanisms of the glomerular endothelium
肾小球内皮的新调节机制
- 批准号:
10621339 - 财政年份:2019
- 资助金额:
$ 47.5万 - 项目类别:
Novel regulatory mechanisms of the glomerular endothelium
肾小球内皮的新调节机制
- 批准号:
10433893 - 财政年份:2019
- 资助金额:
$ 47.5万 - 项目类别:
Novel regulatory mechanisms of the glomerular endothelium
肾小球内皮的新调节机制
- 批准号:
10189577 - 财政年份:2019
- 资助金额:
$ 47.5万 - 项目类别:
Multiphoton microscope replacement for USC shared resource
多光子显微镜替代南加州大学共享资源
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9274881 - 财政年份:2017
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$ 47.5万 - 项目类别:
Novel imaging approach to study podocyte function in vivo
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- 批准号:
9298641 - 财政年份:2014
- 资助金额:
$ 47.5万 - 项目类别:
Novel imaging approach to study podocyte function in vivo
研究体内足细胞功能的新成像方法
- 批准号:
9097687 - 财政年份:2014
- 资助金额:
$ 47.5万 - 项目类别:
Novel imaging approach to study podocyte function in vivo
研究体内足细胞功能的新成像方法
- 批准号:
8815535 - 财政年份:2014
- 资助金额:
$ 47.5万 - 项目类别:
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