RENALASE IN ACUTE KIDNEY INJURY: UTILITY AS A BIOMARKER, AND THERAPEUTIC AGENT

急性肾损伤中的肾酶：作为生物标志物和治疗剂的实用性

• 批准号: 7820609
• 负责人: Gary V. Desir
• 金额: $ 50万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7820609
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Affect; Area; Biological Markers; Biopsy; Blood; Cardiac; Cardiac Surgery procedures; Catecholamines; Clinical; Clinical Trials; Creatinine; Data; Databases; Development; Diagnosis; Disease; Dopamine; Enzyme-Linked Immunosorbent Assay; Epinephrine; Event; Excretory function; Functional disorder; Funding; Future; Gelatinase A; Goals; Hour; Human; Injury; Interleukin-18; Ischemia; Kidney; Laboratories; Measurement; Measures; Methodology; Methods; Monitor; Myocardial; Myocardial Ischemia; National Institute of Diabetes and Digestive and Kidney Diseases; Necrosis; Norepinephrine; Operative Surgical Procedures; Organ; Patients; Pharmaceutical Preparations; Procedures; Proximal Kidney Tubules; Rattus; Recombinants; Renal function; Reperfusion Therapy; Risk; Rodent; Rodent Model; Sensitivity and Specificity; Sepsis; Serum; Severities; Staging; Testing; Therapeutic; Therapeutic Agents; Tissues; Treatment Protocols; Tribes; United States National Institutes of Health; Urine; Validation; Western Blotting; amine oxidase; base; design; diagnostic accuracy; effective therapy; epidemiologic data; falls; high risk; improved; intravenous administration; mortality; mouse model; novel; novel diagnostics; public health relevance; renal ischemia; urinary

DESCRIPTION (provided by applicant): The challenge area (03-DK-102) is the development and validation of novel, noninvasive methods to detect and monitor disorders of relevance to NIDDK at early stages of disease before major organ damage and dysfunction has occurred. Novel diagnostic methodologies relevant to disorders that are currently difficult to detect early in the course of disease and/or that require invasive procedures (such as tissue or organ biopsies) are of highest priority. The specific challenge topic is the development of early, sensitive, non-invasive methods to diagnose acute kidney injury. We propose to examine utility of renalase, a novel molecule discovered in our laboratory, as an early and sensitive biomarker for acute kidney injury. Acute kidney injury (AKI) is a clinical condition commonly associated with sepsis, surgery, and certain drugs, and which affects up to 20% of hospitalized patients. Epidemiologic data indicate those who develop AKI are more likely to die than those who don't, and the risk is proportional to the severity of the renal injury and of the concomitant reduction in renal function. The development of effective treatment protocols for AKI has been hampered by the fact the diagnosis relies heavily of serum creatinine measurements, and is, therefore, often made 48-72 hours following the original insult. There is a clear and pressing need to identify patients with AKI early, and the best approach is believed to involve the identification biomarkers and their validation in human clinical trials. Renalase is an amine oxidase that metabolizes catecholamines such as dopamine, epinephrine and norepinephrine. It is synthesized by the renal proximal tubule, secreted in blood and continuously excreted in urine in the basal state. Renalase levels can be measured either by Western blot or ELISA. Preliminary data suggest that renalase is a novel biomarker for AKI. Moderately severe ischemic insults (global ischemia for 45 min), caused a dramatic and long-lasting decrease in urinary renalase excretion. These data are very exciting and suggest that urinary renalase may be an early biomarker for ischemic AKI. The main goal of this proposal is test the hypothesis that urinary renalase can serve as an early and sensitive biomarker for AKI in rodents, and that renalase administration is a useful therapeutic option to treat AKI in rodents. If the proposed studies are successful, future studies (not part of this proposal) will aim to validate renalase as a biomarker of AKI in humans using the TRIBE-AKI database and or similar available databases, and to test the therapeutic utility of recombinant renalase in AKI in humans. PUBLIC HEALTH RELEVANCE: Acute kidney injury (AKI), a clinical condition commonly associated with sepsis, surgery, and certain drugs, affects up to 20% of hospitalized patients and is associated with increased mortality. The development of effective treatment protocols for AKI has been hampered by the fact the diagnosis relies heavily of serum creatinine measurements, and is, therefore, often made 48-72 hours following the original insult. There is a clear and pressing need to identify patients with AKI early, and the best approach is believed to involve the identification biomarkers and their validation in human clinical trials.

描述（由申请人提供）：挑战区域（03-DK-102）是在发生重大器官损伤和功能障碍之前，在疾病早期阶段检测和监测与NIDDK相关的新型无创方法的开发和验证。与目前在疾病早期难以检测到的疾病和/或需要侵入性手术（例如组织或器官活检）相关的疾病相关的新型诊断方法。具体的挑战主题是开发早期，敏感，无创方法来诊断急性肾脏损伤。我们建议研究肾酶的效用，肾酶是一种在我们的实验室中发现的新型分子，作为急性肾脏损伤的早期敏感生物标志物。急性肾脏损伤（AKI）是一种临床状况，通常与败血症，手术和某些药物有关，可影响多达20％的住院患者。流行病学数据表明，发展为AKI的人比没有死亡的人更有可能死亡，并且这种风险与肾脏损伤的严重程度和肾功能的同时减少的风险成正比。诊断严重依赖血清肌酐测量值的事实阻碍了AKI的有效治疗方案的制定，因此经常在原始侮辱后48-72小时进行。明确而紧迫的需求需要尽早识别患有AKI的患者，而最佳方法被认为涉及鉴定生物标志物及其在人类临床试验中的验证。肾酶是一种胺氧化酶，可以代谢儿茶酚胺，例如多巴胺，肾上腺素和去甲肾上腺素。它是由肾近端小管合成的，在血液中分泌，并在基底状态下尿液中不断排泄。肾小球酶水平可以通过Western印迹或ELISA测量。初步数据表明，肾酶是AKI的新型生物标志物。中度严重的缺血性损伤（全球性缺血45分钟），导致尿肾酶排泄量显着下降。这些数据非常令人兴奋，表明尿肾酶可能是缺血性AKI的早期生物标志物。该提案的主要目的是检验以下假设：尿肾酶可以作为啮齿动物AKI的早期和敏感生物标志物，而肾酶给药是治疗啮齿动物AKI的有用治疗选择。如果提出的研究成功，未来的研究（不是本提案的一部分）将旨在使用Tribe-Aki数据库和 /或类似可用的数据库来验证人类AKI的生物标志物，并测试人类AKI重组肾酶的治疗效率。 公共卫生相关性：急性肾脏损伤（AKI），这是一种临床状况，通常与败血症，手术和某些药物有关，会影响高达20％的住院患者，并且与死亡率的增加有关。诊断严重依赖血清肌酐测量值的事实阻碍了AKI的有效治疗方案的制定，因此经常在原始侮辱后48-72小时进行。明确而紧迫的需求需要尽早识别患有AKI的患者，而最佳方法被认为涉及鉴定生物标志物及其在人类临床试验中的验证。