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: 10301616
• 负责人: Kaice LaFavers
• 金额: $ 9.15万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-10 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10301616
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Animal Model; Anti-Inflammatory Agents; Area; Bioinformatics; Biological Response Modifiers; Biology; Blood Circulation; Breeding; Cardiovascular Diseases; Chronic Kidney Failure; Communication; Constitutional; Critical Care; Critical Illness; Data; Disease; Doctor of Philosophy; Electrolytes; Faculty; Failure; Foundations; Functional disorder; Genetic; Genetic Models; Goals; Grant; 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; Lead; Life; Macrophage Activation; Manuscripts; Mediating; Mentors; Mentorship; Modeling; Molecular; Mononuclear; Morbidity - disease rate; Mouse Protein; 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; base; cardiovascular infection; career; career development; cecal ligation puncture; cohort; cytokine; design; experimental study; human model; immunoregulation; improved; in vivo; individualized medicine; kidney preservation; macrophage; 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.

这个K99/R 00应用程序从Kaice A LaFavers博士，旨在获得知识， 过渡到领导研究项目的独立教师职位所需的培训 重点关注脓毒症和严重感染情况下的肾器官串扰。败血症是一 宿主对感染的反应失调，是发病率和死亡率的主要因素 国际吧当急性肾损伤（阿基）发生在脓毒症的情况下，死亡率翻了一番， 大约1/2的患者。我们最近有证据表明源自肾脏的塔姆·霍斯福尔 蛋白质（THP）对脓毒症死亡率具有保护作用。THP从肾脏分泌，主要进入 尿液中，它是最丰富的蛋白质成分。然而，一小部分THP产生于 肾分泌到肾间质中，在那里它进入循环。增加水平的 血清THP最近与降低死亡率和预防慢性 肾脏疾病的研究。循环THP也已成为免疫调节剂， THP的遗传缺失导致单核吞噬细胞的数量和功能减少， 肾脏在阿基的人类和动物模型中，THP在损伤后不久就急剧耗尽。 在目前的提议中，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，增强巨噬细胞功能和信号传导。这 假设将通过两个具体目标进行检验。一个目标是确定由释放的循环THP 肾是脓毒症中的关键保护分子，使用THP消耗的基因敲除模型， 鼠败血症这一目标也将确定用外源性THP治疗脓毒症小鼠的潜力 来改善败血症的预后第二个目的将确定THP对增强巨噬细胞的作用， 通过评估体内吞噬作用、巨噬细胞活化和信号传导以及巨噬细胞- 衍生的IL-15依赖性信号传导。在Tarek Ashkar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。这种额外的训练 将在技术技能发展领域，包括生物信息学，先进的成像， 分析、蛋白质纯化、小鼠模型开发和育种，沿着专业的 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， 她的第一个R 01提交和建立一个独立的职业生涯。