The protective role of kidney-derived Tamm Horsfall protein (Uromodulin) in sepsis

肾源性 Tamm Horsfall 蛋白（尿调节蛋白）在脓毒症中的保护作用

• 批准号: 10886979
• 负责人: Kaice LaFavers
• 金额: $ 24.9万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10886979
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Animal Model; Anti-Inflammatory Agents; Area; Bioinformatics; Biological Response Modifiers; Biology; Breeding; Cardiovascular Diseases; Chronic Kidney Failure; Circulation; Communication; Constitution; Constitutional; Critical Care; Critical Illness; Data; Disease; Doctor of Philosophy; Electrolytes; Faculty; Failure; Foundations; Functional disorder; Genetic; Genetic Models; Goals; Grant; Hospitalization; Human; Image; Immune System Diseases; Immune response; Immune system; In Vitro; Incidence; Infection; Inflammatory; Injury; Injury to Kidney; Innate Immune System; Interleukin-15; Investments; Kidney; Knock-out; Knockout Mice; Knowledge; Knowledge acquisition; Life; Macrophage; Macrophage Activation; Manuscripts; Mediating; Mentors; Mentorship; Modeling; Molecular; Mononuclear; Morbidity - disease rate; Mus; Organ; Organ failure; Outcome; Oxidative Stress; Pathogenesis; Patient-Focused Outcomes; Patients; Phagocytes; Phagocytosis; Play; Positioning Attribute; Production; Protein Deficiency; Proteins; Publishing; Renal function; Research; Research Personnel; Risk; Role; Science; Sepsis; Septic Shock; Serum; Severities; Signal Transduction; Technical Expertise; Testing; Therapeutic; Therapeutic Uses; Training; UMOD gene; Urine; Work; Writing; cardiovascular infection; career; career development; cecal ligation puncture; cohort; cytokine; design; experimental study; human model; immunoregulation; improved; in vivo; individualized medicine; kidney preservation; model development; mortality; mortality risk; mouse model; novel; organ injury; post-doctoral training; programs; protective effect; protein purification; response; septic; skill acquisition; tool

This K99/R00 application from Kaice A LaFavers, PhD, is designed to acquire the knowledge and training necessary to transition to an independent faculty position leading a research program focused on kidney-organ cross talk in the setting of sepsis and severe infection. Sepsis is a dysregulated host response to infection and is a major contributor to morbidity and mortality worldwide. When acute kidney injury (AKI) occurs in the setting of sepsis, mortality doubles to approximately 1 in 2 patients. We have recent evidence that the kidney-derived Tamm Horsfall Protein (THP) is protective against sepsis mortality. THP is secreted from the kidney primarily into the urine, where it is the most abundant protein component. However, a small portion of THP produced in the kidney is secreted into the kidney interstitium, where it enters the circulation. Increased levels of serum THP have recently been associated with decreased mortality and protection against chronic kidney disease in human cohorts. Circulating THP has also emerged as an immune regulator, with genetic depletion of THP leading to decreased number and function of mononuclear phagocytes in the kidney. In both human and animal models of AKI, THP is acutely depleted shortly following injury. In the current proposal, the overall hypothesis is that the kidney protects other organs during sepsis by releasing THP in the circulation, where it enhances macrophage function and signaling. This hypothesis will be tested by two specific aims. One aim will establish that circulating THP released by the kidney is a key protective molecule in sepsis using a genetic knockout model of THP depletion in murine sepsis. This aim will also determine the potential of treating septic mice with exogenous THP to improve sepsis outcomes. The second aim will define the effect of THP on enhancing macrophage function by assessing in vivo phagocytosis, macrophage activation and signaling, and macrophage- derived IL-15-dependent signaling in sepsis. Under the mentorship of Dr. Tarek Ashkar, Dr. LaFavers extends her current research on THP biology and proposes additional training. This additional training will be in the areas of technical skill development, including bioinformatics, advanced imaging analytics, protein purification, mouse model development and breeding, along with professional career development in science communication, lab management, grant/manuscript writing and mentoring. The completion of this proposal will provide Dr. LaFavers with the expertise and training for her first R01 submission and the establishment of an independent career.

Kaice A LaFavers 博士的 K99/R00 应用程序旨在获取知识和 过渡到领导研究项目的独立教职职位所需的培训 专注于脓毒症和严重感染情况下的肾脏器官交互作用。败血症是一种 宿主对感染的反应失调，是发病率和死亡率的主要原因 全世界。当脓毒症发生急性肾损伤 (AKI) 时，死亡率会翻倍 大约二分之一的患者。我们最近有证据表明，肾源性 Tamm Horsfall 蛋白质 (THP) 可以预防脓毒症死亡。 THP 主要从肾脏分泌到 尿液中，它是最丰富的蛋白质成分。然而，一小部分 THP 是在 肾脏分泌到肾间质，并在那里进入循环。增加的水平 最近，血清 THP 与降低死亡率和预防慢性病有关 人类肾脏疾病。循环 THP 也已成为一种免疫调节剂， THP 基因缺失导致单核吞噬细胞数量和功能下降 肾脏。在 AKI 的人类和动物模型中，THP 在受伤后不久就会急剧耗尽。 在当前的提案中，总体假设是肾脏在脓毒症期间保护其他器官 通过在循环中释放 THP，增强巨噬细胞的功能和信号传导。这 假设将通过两个具体目标进行检验。目标之一是确定由 使用THP耗竭的基因敲除模型，肾脏是脓毒症的关键保护分子 鼠败血症。这一目标还将确定用外源性 THP 治疗脓毒症小鼠的潜力 改善败血症的结果。第二个目标将确定 THP 对增强巨噬细胞的作用 通过评估体内吞噬作用、巨噬细胞激活和信号传导以及巨噬细胞- 脓毒症中衍生的 IL-15 依赖性信号传导。在 Tarek Ashkar 博士、LaFavers 博士的指导下 扩展了她目前对 THP 生物学的研究，并提出了额外的培训。此次额外培训 将在技术技能开发领域，包括生物信息学、高级成像 分析、蛋白质纯化、小鼠模型开发和育种以及专业 科学传播、实验室管理、资助/手稿写作和 指导。该提案的完成将为 LaFavers 博士提供专业知识和培训 表彰她首次提交 R01 并建立独立职业生涯。