Acute inhibition of renal gene expression to prevent nephrotoxicity.

急性抑制肾脏基因表达以防止肾毒性。

基本信息

批准号：
9752579
负责人：
Michael Thomas Eadon
金额：
$ 15.65万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9752579
关键词：
Acute Acute Renal Failure with Renal Papillary Necrosis Address Affect Animal Model Appointment Award Biological Markers Biopsy Candidate Disease Gene Caring Cells Cisplatin Clinic Clinical Clinical Pharmacology Clinical Trials Clinical and Translational Science Awards Clofarabine Colistin Databases Development Drug Modelings Drug toxicity Drug usage Environment Equilibrium Expenditure Exposure to Failure Fellowship Foundations Funding Future Gene Expression Gene Targeting Genes Genetic Genetic Databases Genetic Markers Genetic Models Genome Gentamicins Glomerulonephritis Goals Grant Head Human Indiana Injury Injury to Kidney Intervention Kidney Kidney Diseases Knockout Mice LDL-Receptor Related Protein 2 Laboratories Lasers Learning Learning Skill Length of Stay Life Malignant Neoplasms Medical Membrane Mentors Methylation Microdissection Modeling Molecular Mus Nephrology Nephrons Outcome POU2F1 gene Pathway interactions Patients Pharmaceutical Preparations Pharmacogenomics Phase Phase I Clinical Trials Phase II Clinical Trials Physicians Population Genetics Premedication Prevention Prevention strategy Proteins Proximal Kidney Tubules Recording of previous events Research Personnel Role Saline Schools Scientist Site Small Interfering RNA TP53 gene Techniques Testing Therapeutic Time Tissues Toxic effect Training Translating Translations Tubular formation United States National Institutes of Health Universities Validation analytical method clinical care clinical practice clinically relevant cytotoxicity experience genetic approach in vivo inpatient service knock-down medical schools mortality mouse model nephrotoxicity novel novel strategies preclinical study prevent public health relevance success therapeutic siRNA therapeutic target uptake

项目摘要

DESCRIPTION (provided by applicant): Acute inhibition of renal gene expression to prevent nephrotoxicity Prevention of AKI is of paramount importance, but success has been limited when approaches are applied generally. A key reason for these failures is a lack of targets specific to a given cause of AKI. This project utilizes a population genetics model to identify genes associated with sensitivity to four clinically relevant nephrotoxins: gentamicin, colistin, cisplatin, and clofarabine. In this proposal, we seek to validate the success of this population genetics model with acute in vivo siRNA inhibition of renal gene expression. The efficacy of target gene inhibition will be tested in corresponding murine models of drug-induced AKI to determine if this therapeutic strategy mitigates nephrotoxicity. A secondary aim of this project is to discern if acute inhibition of candidate transport genes similarly prevents nephrotoxicity by inhibiting proximal tubular uptake of gentamicin, colistin, cisplatin, or clofarabine. The expected outcome is to determine an optimal nephrotoxicity prevention strategy for each drug. The approach will be paradigm shifting - bringing a drug-specific intervention to each form of renal injury. The precedent for premedication to prevent nephrotoxicity is used in clinical practice as saline is often given to prevent contrast nephropathy. Thus, the siRNA strategies outlined in this proposal hold clinical relevance and the potential to translate to clinical trials. This approach wll yield multiple new molecular therapeutics specific to a variety of nephrotoxins, ready for rapid translation to clinical trials. My long-term goal is to become a physician scientist using large databases to uncover and validate genetic biomarkers and therapeutic targets which will readily translate to clinical care. Through this K08 award, I will learn new techniques including: analytic methods for genetic databases, animal model experimentation, laser micro-dissection (LMD), and in vivo siRNA knockdown. The acquired techniques will allow me to complete the above aims, but also provide the foundation to successfully compete for future R01 funding to: 1) uncover biomarkers from large genetic databases, 2) determine nephron segment specific gene expression with LMD of biopsy tissue, and 3) test mechanistic pathways and therapeutic targets in vivo with siRNA inhibition. These techniques can be applied to the improvement of renal care for many conditions. Further, the mentoring team I have assembled will advise me on the translation of these siRNA constructs to future clinical trials. My mentors and advisors at the Indiana University School of Medicine (IUSM) have a previous history of translating their pre-clinical studies with siRNA to successful phase 1 and 2 clinical trials. The rich environment at IUSM is sure to aid in my development as a physician scientist. With a dual appointment in the divisions of nephrology and clinical pharmacology, I am exposed to a wide range of collaborators in nearly every primary division. My division heads, Sharon Moe and David Flockhart, effectively protect my time as my clinical obligations are limited to 4 weeks of inpatient service and 1/2 day of clinic. They have provided ample laboratory space, start-up funds, and a technician. Our school renewed its NIH Clinical Translational Science Award (the Indiana CTSI) in 2013. I have already reaped the benefits of this advantage by obtaining a CTSI biomedical researcher grant. Finally, my mentors, Pierre Dagher and Todd Skaar, are incredibly supportive. The two of them provide a balance so I learn skills in both mouse models of acute kidney injury and pharmacogenomics analysis / validation. In summary, the proposed project builds logically on my fellowship training in nephrology and clinical pharmacology. My transition to Indiana University School of Medicine makes a great deal of sense not only because of its institutional commitment to me, but also what I can learn from my selected mentors, Drs. Pierre Dagher, Todd Skaar, and David Flockhart in order to address my specific aims and hypothesis. With ties to clinical pharmacology and nephrology, I am poised to apply novel strategies to nephrotoxicity prevention and other kidney diseases.

描述（由申请人提供）：急性抑制肾脏基因表达以防止肾毒性预防AKI至关重要，但是当采用方法通常采用方法时，成功受到限制。这些失败的关键原因是缺乏针对AKI原因的目标。该项目利用种群遗传学模型来识别与对四种临床相关肾毒素敏感性相关的基因：庆大霉素，colistin，cisplatin和clofarabine。在此提案中，我们试图通过急性体内siRNA抑制肾脏基因表达的急性验证该种群遗传学模型的成功。靶基因抑制的功效将在相应的药物诱导的AKI的鼠模型中进行测试，以确定这种治疗策略是否会减轻肾毒性。该项目的第二个目标是为了辨别急性抑制候选转运基因是否类似地通过抑制庆大霉素，colistin，cisplatin或clofarabine的近端管状摄取来防止肾毒性。预期结果是确定每种药物的最佳肾毒性预防策略。该方法将是范式转移 - 将药物特异性干预带入每种形式的肾脏损伤。预防肾毒性的预言的先例用于临床实践中，因为盐水通常被给予防止造影剂肾病。因此，该提案中概述的siRNA策略具有临床相关性和转化为临床试验的潜力。这种方法WLL产生了针对多种肾毒素特有的多种新分子疗法，可以快速转化为临床试验。我的长期目标是成为一名使用大型数据库的医师科学家，以发现和验证遗传生物标志物和治疗靶标，这将很容易转化为临床护理。通过这个K08奖，我将学习新技术，包括：分析遗传数据库的方法，动物模型实验，激光显微脱落（LMD）和体内siRNA敲低的方法。获得的技术将使我能够完成上述目标，但也为成功竞争未来的R01资金提供了基础：1）从大遗传数据库中揭示生物标志物，2）确定用活检组织LMD的肾单位段特定基因表达，以及3）测试机械途径和治疗途径和治疗型靶标在Vivo in vivo in vivo in vivo insirna insirna insirna insirna Inibitions。这些技术可以应用于在许多情况下改善肾脏护理。此外，我组装的指导团队将向我提供有关将这些siRNA构造转换为将来临床试验的建议。我的印第安纳大学医学院（IUSM）的导师和顾问有一个以前的历史，即将其与siRNA进行临床前研究转换为成功的第1阶段和2阶段的临床试验。 IUSM的丰富环境肯定会帮助我作为医师科学家的发展。通过在肾脏病和临床药理学的分区中进行双重任命，我几乎在每个主要部门中都接触了广泛的合作者。我的部门负责人Sharon Moe和David Flockhart有效地保护了我的时间，因为我的临床义务仅限于4周的住院服务和1/2天的诊所。他们提供了足够的实验室空间，启动资金和技术人员。我们的学校于2013年恢复了其NIH临床转化科学奖（印第安纳州CTSI）。我已经通过获得CTSI生物医学研究员的赠款来获得这一优势的好处。最后，我的导师皮埃尔·达格（Pierre Dagher）和托德·斯卡尔（Todd Skaar）非常支持。他们两个提供了平衡，因此我学习了急性肾脏损伤的小鼠模型和药物基因组学分析 /验证的技能。总而言之，拟议的项目以我在肾脏病和临床药理学方面的奖学金培训为基础。我向印第安纳大学医学院的过渡具有很大的意义，这不仅是因为它对我的机构承诺，而且还可以从选定的导师Drs中学到的东西。 Pierre Dagher，Todd Skaar和David Flockhart为了解决我的具体目标和假设。与临床药理学和肾脏病联系，我准备将新型策略应用于预防肾毒性和其他肾脏疾病。