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患者发展为AKI，并与50％的死亡率RTE相关。 单一发生的AKI易于患者发展慢性疾病，例如慢性肾脏疾病 （CKD）和终阶段肾脏疾病（ESRD），降低生活质量并且可能是致命的条件。 越来越多的研究表明，AKI诱导的损伤促进了持续的肾脏注射和纤维化 驱动到CKD和ESRD。了解肾脏炎症的机制 因此，受监管将允许开发有针对性的肾脏治疗环境。炎 相关的淋巴管生成负责通过吸收液体来维持组织内稳态， 大分子，蛋白质和免疫菌株贩运。在AKI侮辱性淋巴生长因子上 内皮生长因子D（VEGF-D）和VEGF-C在肾脏内增加。淋巴研究具有 鉴定出LEC的免疫调节作用，例如MHC的表达，趋化因子受体和抗原 推介会。该实验室表明，在AKI模型中，肾脏淋巴管生成增加了 免疫细胞的存在并减少肾纤维化。但是，LEC如何调节AKI相关注射 恢复仍然未知。这项研究的长期目标是确定如何免疫调节作用 LEC会影响AKI的肾脏免疫响应和恢复。该提议的总体目标是确定如何 自适应免疫响应在AKI中随着肾脏淋巴密度的增加而改变，以及这些免疫响应如何 删除已知的LEC免疫调节分子后，细胞群会改变。中心假设 是肾脏LEC通过直接淋巴免疫细胞相互作用调节注射并调节免疫 从组织中清除细胞清除，改变了AKI中的病理生理结果。由强烈支持 初步数据该假设将通过两个具体目标检验：目标1确定肾脏如何增加 淋巴管生成改变了AKI中的适应性免疫响应。 AIM 2证明了特定的删除 鞘氨醇1-磷酸（S1P）分泌改变了AKI中T细胞反应和炎症分辨率。在 AKI的第一个目标顺铂和缺血 - 灌注（IR）模型将评估肾脏淋巴密度是否增加 在肾脏特异性诱导的VEGF-D（KIDVD）的肾脏特异性诱导过表达的小鼠模型中受伤之前 免疫细胞群体和炎症进展。初步数据表明肾脏淋巴增加增加 密度素数适应性免疫反应并减轻肾纤维化。对于第二个目标，确定 S1P的特异性缺失，生物活性，改变肾脏免疫核管清除和自适应免疫 AKI中的反应可能会提供一种新型的肾脏靶向治疗选择。解决LEC如何调节AKI 相关感染和恢复淋巴特定遗传模型，肾损伤模型的组合， 免疫球表型将确定肾脏免疫球对AKI反应的改变。