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 LaFivers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员职位所需的培训 重点介绍了脓毒症和严重感染环境下的肾-器官串扰。败血症是一种 宿主对感染的反应失调，是导致发病率和死亡率的主要因素 全世界。当脓毒症时发生急性肾损伤(AKI)时，死亡率增加一倍至 大约每2个患者中就有1个。我们最近有证据表明肾脏来源的塔姆·霍斯费尔 蛋白质(THP)对脓毒症死亡率具有保护作用。THP主要从肾脏分泌到 尿液是最丰富的蛋白质成分。然而，一小部分THP生产于 肾脏被分泌到肾间质，在那里它进入循环。增加了 最近，血清THP与降低死亡率和预防慢性疾病有关 人类队列中的肾脏疾病。循环中的THP也成为一种免疫调节剂， THP基因缺失导致小鼠单核巨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。 在目前的方案中，总体假设是在脓毒症期间肾脏保护其他器官。 通过在循环中释放THP，增强巨噬细胞的功能和信号。这 假设将通过两个具体的目标进行检验。一个目标是建立流通中的THP，由 肾脏是脓毒症的关键保护分子，采用THP耗竭的基因敲除模型 小鼠败血症。这一目标还将确定外源性THP治疗脓毒症小鼠的潜力 以改善败血症的结局。第二个目标将确定THP对增强巨噬细胞的作用 通过评估体内吞噬功能，巨噬细胞激活和信号，以及巨噬细胞- 脓毒症中衍生的IL-15依赖信号转导。在塔里克·阿什卡博士的指导下，拉法弗斯博士 扩展了她目前对THP生物学的研究，并建议进行额外的培训。这项额外的培训 将在技术技能发展领域，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，以及专业人员 在科学传播、实验室管理、补助金/手稿写作和 辅导。这项提案的完成将为拉法弗斯博士提供专业知识和培训 为她的第一个R01提交和建立一个独立的职业生涯。