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：
9531353
负责人：
Michael Thomas Eadon
金额：
$ 15.67万
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/9531353
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预防肾毒性预防 AKI 至关重要，但普遍应用方法时成功率有限。这些失败的一个关键原因是缺乏针对特定 AKI 原因的目标。该项目利用群体遗传学模型来识别与四种临床相关肾毒素敏感性相关的基因：庆大霉素、粘菌素、顺铂和氯法拉滨。在本提案中，我们试图通过体内 siRNA 对肾脏基因表达的急性抑制来验证该群体遗传学模型的成功。将在相应的药物诱导 AKI 小鼠模型中测试靶基因抑制的功效，以确定该治疗策略是否可以减轻肾毒性。该项目的第二个目标是以确定候选转运基因的急性抑制是否同样通过抑制庆大霉素、粘菌素、顺铂或氯法拉滨的近端肾小管摄取来预防肾毒性。预期的结果是确定每种药物的最佳肾毒性预防策略。该方法将发生范式转变——对每种形式的肾损伤进行药物特异性干预。在临床实践中采用术前用药来预防肾毒性的先例，因为通常给予生理盐水来预防造影剂肾病。因此，本提案中概述的 siRNA 策略具有临床相关性并具有转化为临床试验的潜力。这种方法将产生针对多种肾毒素的多种新分子疗法，为快速转化为临床试验做好准备。我的长期目标是成为一名医师科学家，利用大型数据库来发现和验证遗传生物标志物和治疗靶点，并将其轻松转化为临床护理。通过这个K08奖，我将学习新技术，包括：分析遗传数据库、动物模型实验、激光显微切割 (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，同时也为成功竞争未来的 R01 资金奠定基础：1) 从大型遗传数据库中发现生物标志物，2) 通过活检组织的 LMD 确定肾单位片段特异性基因表达，以及3) 通过 siRNA 抑制测试体内机制途径和治疗靶点。这些技术可应用于改善多种疾病的肾脏护理。此外，我组建的指导团队将为我将这些 siRNA 构建体转化为未来的临床试验提供建议。我在印第安纳大学医学院 (IUSM) 的导师和顾问此前曾将 siRNA 临床前研究成功转化为 1 期和 2 期临床试验。 IUSM 丰富的环境肯定有助于我作为一名医师科学家的发展。由于在肾脏病学和临床药理学部门双重任命，我在几乎每个主要部门都接触到了广泛的合作者。我的部门主管 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 天的门诊服务。他们提供了充足的实验室空间、启动资金和技术人员。我们学校于 2013 年更新了 NIH 临床转化科学奖（印第安纳州 CTSI）。我已经通过获得 CTSI 生物医学研究员补助金而受益于这一优势。最后，我的导师 Pierre Dagher 和 Todd Skaar 给予了我极大的支持。它们两者提供了平衡，因此我学习了急性肾损伤小鼠模型和药物基因组学分析/验证的技能。总之，拟议的项目逻辑上建立在我在肾脏病学和临床药理学方面的进修培训之上。我到印第安纳大学医学院的过渡非常有意义，不仅因为它对我的机构承诺，而且还因为我可以从我选定的导师 Drs. 那里学到东西。 Pierre Dagher、Todd Skaar 和 David Flockhart 来阐述我的具体目标和假设。通过与临床药理学和肾脏病学的联系，我准备将新策略应用于肾毒性预防和其他肾脏疾病。