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.

该Kaice A Lafavers博士的K99/R00应用程序旨在获取知识和 过渡到领导研究计划的独立教师职位所必需的培训 专注于在败血症和严重感染的情况下进行肾脏 - 器官串扰。败血症是 宿主对感染的反应失调，是发病率和死亡率的主要因素 全世界。当急性肾脏损伤（AKI）发生在败血症的情况下，死亡率翻了一番 大约有2例患者中有1个。我们最近有证据表明肾脏衍生的塔姆·霍斯山 蛋白质（THP）可防止败血症死亡率。 THP主要是从肾脏分泌的 尿液，其中是最丰富的蛋白质成分。但是，在 肾脏被分泌到肾脏间质中，进入循环。增加的水平 血清THP最近与死亡率降低和针对慢性有关 人类人群中的肾脏疾病。循环THP也已成为免疫调节剂， THP的遗传耗竭导致单核吞噬细胞数量和功能减少 肾脏。在AKI的人类和动物模型中，THP受伤后不久就会急剧耗尽。 在当前的提议中，总体假设是肾脏在败血症期间保护其他器官 通过在循环中释放THP，从而增强了巨噬细胞功能和信号传导。这 假设将通过两个具体目标检验。一个目的将确定该发行的THP 肾脏是败血症中的关键保护分子，使用THP耗竭的遗传基因敲除模型 鼠败血症。该目标还将决定用外源性THP治疗化粪池小鼠的潜力 改善败血症的结果。第二个目标将定义THP对增强巨噬细胞的影响 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 - 败血症中衍生的IL-15依赖性信号传导。在Tar​​ek Ashkar博士的指导下，Lafavers博士 扩展了她目前对THP生物学的研究，并提出了额外的培训。这项额外的培训 将处于技术技能开发领域，包括生物信息学，高级成像 分析，蛋白质纯化，小鼠模型开发和繁殖以及专业 科学传播，实验室管理，赠款/手稿写作中的职业发展和 指导。该提案的完成将为Lafavers博士提供专业知识和培训 对于她的第一次R01提交和建立独立职业。