lmmunomodulatory roles of renal lymphatic endothelial cells in Acute Kidney Injury

肾淋巴内皮细胞在急性肾损伤中的免疫调节作用

• 批准号: 10612171
• 负责人: Heidi Creed
• 金额: $ 3.63万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-30 至 2025-05-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10612171
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Address; Admission activity; Affect; Agonist; Antigen Presentation; Attenuated; Automobile Driving; Binding; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cardiorenal syndrome; Cell Communication; Cell Differentiation process; Cell Survival; Cell secretion; Cells; Chronic; Chronic Kidney Failure; Cisplatin; Culture Techniques; Data; Development; Disease model; End stage renal failure; Environment; Fibrosis; Flow Cytometry; Future; Genetic Models; Goals; Health; Heart Injuries; Homeostasis; Hospitalization; Immune; Immune response; Inflammation; Inflammatory; Inflammatory Response; Injury; Injury to Kidney; Interferon Type II; Ischemia; Kidney; Kidney Diseases; Length; Lipids; Liquid substance; Lymphangiogenesis; Lymphatic; Lymphatic Endothelial Cells; Lymphatic Research; Lymphocyte; Malignant Neoplasms; Medical Care Costs; Modeling; Molecular; Mus; Outcome; Pathway interactions; Patients; Phenotype; Play; Population; Positioning Attribute; Postdoctoral Fellow; Proteins; Quality of life; RNA; Recovery; Regulatory T-Lymphocyte; Renal function; Reperfusion Therapy; Research; Resolution; Resources; Risk; Role; Secure; Signal Pathway; Signal Transduction; Skin; Sphingosine-1-Phosphate Receptor; Spleen; T cell response; T memory cell; T-Lymphocyte; Testing; Therapeutic; Tissues; United States; United States National Institutes of Health; VEGFC gene; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor D; Vascular Endothelial Growth Factors; adaptive immune response; career networking; chemokine receptor; density; immune activation; immunoregulation; improved; inflammatory milieu; injured; kidney fibrosis; lymph nodes; lymphatic vasculature; lymphatic vessel; lymphocyte trafficking; macromolecule; melanoma; mortality; mouse model; novel; overexpression; prevent; programmed cell death ligand 1; receptor expression; response; single-cell RNA sequencing; skills; sphingosine 1-phosphate; targeted treatment; trafficking; uptake

PROJECT SUMMARY In the United States an estimated 50% of ICU patients develop AKI and is associated with a 50% mortality rte. A single occurrence of AKI predisposes a patient to develop chronic conditions such as Chronic Kidney Disease (CKD) and End-Stage Renal Disease (ESRD), conditions which decrease quality of life and may be fatal. Increasingly, research demonstrates that AKI induced injury promotes persistent renal inflammation and fibrosis driving progression to CKD and ESRD. Understanding mechanisms by which renal inflammation may be regulated would therefore allow development of targeted renal therapeutic environments. Inflammation associated lymphangiogenesis is responsible for maintaining tissue homeostasis through uptake of fluids, macromolecules, proteins, and immune cell trafficking. Upon AKI insult lymphatic growth factors Vascular endothelial growth factor D (VEGF-D) and VEGF-C are increased within the kidney. Lymphatic research has identified immunomodulatory roles of LECs such as expression of MHCs, chemokine receptors, and antigen presentation. The lab has demonstrated increased renal lymphangiogenesis in models of AKI alters adaptive immune cell presence and reduces renal fibrosis. However, how LECs regulate AKI associated inflammation and recovery is still unknown. The long-term goal of this study is to identify how immunomodulatory roles of LECs impact the renal immune response and recovery in AKI. The proposal’s overall objective is to identify how the adaptive immune response is altered in AKI with increased renal lymphatic density and how these immune cell populations are altered upon deletion of a known LEC immunomodulatory molecule. The central hypothesis is that renal LECs regulate inflammation through direct lymphatic-immune cell interactions and regulate immune cell clearance from the tissue, altering pathophysiological outcomes in AKI. Directed by strongly supportive preliminary data the hypothesis will be tested by two specific aims: Aim 1 Identify how increased renal lymphangiogenesis alters the adaptive immune response in AKI. Aim 2 Demonstrate LEC specific deletion of sphingosine-1-phosphate (S1P) secretion alters the T cell response and inflammation resolution in AKI. In the first aim cisplatin and ischemia-reperfusion (IR) models of AKI will assess if increased renal lymphatic density prior to injury in a mouse model of kidney specific inducible overexpression of VEGF-D (KidVD) alters adaptive immune cell populations and inflammatory progression. Preliminary data suggests increased renal lymphatic density primes the adaptive immune response and attenuates renal fibrosis. For the second aim, determining how a LEC specific deletion of S1P, a bioactive, alters renal immune cell clearance and the adaptive immune response in AKI may provide a novel renal targeted therapeutic option. To address how LECs regulate AKI associated inflammation and recovery a combination of lymphatic specific genetic models, renal injury models, and immune cell phenotyping will identify alterations in the renal immune cell response to AKI.

项目摘要 在美国，估计有50%的ICU患者发生阿基，并与50%的死亡率相关。 单次发生阿基使患者易于发展慢性疾病，如慢性肾病 (CKD)和终末期肾病（ESRD），降低生活质量并可能致命的病症。 越来越多的研究表明，阿基诱导的损伤会促进持续性肾脏炎症和纤维化 导致CKD和ESRD进展。了解肾脏炎症可能是 因此，受监管的药物将允许开发靶向肾脏治疗环境。炎症 相关的淋巴管生成负责通过摄取液体维持组织体内平衡， 大分子、蛋白质和免疫细胞运输。阿基损伤后淋巴生长因子血管 内皮生长因子D（VEGF-D）和VEGF-C在肾内增加。淋巴系统的研究 已确定LEC的免疫调节作用，如MHC、趋化因子受体和抗原的表达 演示文稿.该实验室已经证明，在阿基模型中增加的肾淋巴管生成改变了适应性 免疫细胞的存在和减少肾纤维化。然而，LEC如何调节阿基相关炎症 恢复情况仍然未知。这项研究的长期目标是确定免疫调节作用如何， LEC影响阿基中的肾免疫应答和恢复。该提案的总体目标是确定如何 阿基中的适应性免疫应答随着肾淋巴密度的增加而改变， 细胞群在已知LEC免疫调节分子缺失后发生改变。核心假设 肾LEC通过直接炎症-免疫细胞相互作用调节炎症， 从组织中清除细胞，改变阿基的病理生理结果。导演大力支持 初步数据的假设将通过两个具体的目标进行测试：目标1确定如何增加肾 淋巴管生成改变阿基中的适应性免疫应答。目的2证明LEC特异性缺失 鞘氨醇-1-磷酸（S1 P）分泌改变了阿基中的T细胞应答和炎症消退。在 阿基的第一目标顺铂和缺血-再灌注（IR）模型将评估肾淋巴管密度增加是否 在肾特异性诱导VEGF-D过表达（KidVD）的小鼠模型中， 免疫细胞群和炎症进展。初步数据显示肾淋巴管 密度引发适应性免疫应答并减弱肾纤维化。对于第二个目标，确定 LEC特异性缺失S1 P（一种生物活性物质）如何改变肾免疫细胞清除和适应性免疫 阿基的缓解可能提供一种新的肾靶向治疗选择。阐述LEC如何调节阿基 相关炎症和恢复淋巴特异性遗传模型，肾损伤模型， 免疫细胞表型分析将鉴定肾免疫细胞对阿基应答的改变。