The Role of Peroxisome Proliferator Activated Receptor Alpha in Autosomal Dominant Polycystic Kidney Disease

项目摘要 本提案的总体目标是为Ronak博士提供严格的研究和培训经验 Lakhia成为一名独立的医生科学家。申请人是一名委员会认证的肾病学家， 最近在一个独立资助的实验室完成了作为NIH-T32研究员的博士后培训。她 计划提高她的技能，并建立在她的经验，成为一个优秀的医生科学家和 常染色体显性遗传性多囊肾病（ADPKD）和代谢方面的国家公认专家。的 该提案的目的是提出新的科学见解，并允许申请人成长， 通过适当的指导发挥她的全部潜力。她将研究干扰microRNA（miRNA） ADPKD中过氧化物酶体增殖物激活受体α（Ppara）介导的调节。她的研究 提出有可能提供关于代谢重编程的深刻的新见解， 在ADPKD。UT西南是一个世界著名的机构，在执行切割的良好记录- 边缘研究，提供优秀的资源，并培养成功的年轻教师成为他们的领导者， 各自领域候选人已经制定了一个全面的职业发展计划，以补充她 研究目的。候选人的培训目标包括1）代谢表型2）基因编辑和3） 统计学/生物信息学。她的共同导师相互补充，以适当地指导和监督 候选人的研究经验和培训。史蒂芬·克利厄博士是美国国家科学院的成员， 科学，是世界著名的核激素受体和代谢专家。维沙尔·帕特尔医生 肾脏学助理教授，是miRNAs和ADPKD的国际专家。此外，赵博士 Xing，副教授兼UT西南部McDermott生物信息学核心主任，将担任 为申请人的统计/生物信息学培训提供咨询。咨询委员会由4名 模范科学家和医生科学家将为职业生涯提供额外的支持和指导 发展申请人将确定是否阻止miRNA与Ppara 3 '-UTR结合 增强其翻译，改善氧化磷酸化（OXPHOS）和脂肪酸氧化（FAO）， 减弱ADPKD中的囊肿生长。她开发了一套独特的工具来精确地解决她的每一个问题。 具体目标。目的1将确定从Ppara 3 '-UTR缺失miRNA结合位点是否使其正常化。 表达和减缓囊肿生长。目的2将确定是否从Ppara缺失miRNA结合位点 3 '-UTR改善OXPHOS/FAO。目标3将确定Ppara 3 '-UTR靶位点阻断剂是否可以 稳定其表达并减缓囊肿生长。这些研究将共同确立Ppara 3 '-UTR作为药物 靶向ADPKD，并为mRNA转录物的靶向稳定提供原理证明， 治疗方法

Project Summary The overall objective of this proposal is to provide a rigorous research and training experience for Dr. Ronak Lakhia to become an independent physician scientist. The applicant is a board certified nephrologist who recently completed post-doctoral training as a NIH-T32 fellow in an independently funded laboratory. She plans to enhance her skillset and build on her experience to become an excellent physician scientist and a nationally recognized expert in autosomal dominant polycystic kidney disease (ADPKD) and metabolism. The objectives of this proposal are designed to make new scientific insights and allow the applicant to grow and reach her full potential through proper mentorship. She will study the effects of disrupting microRNA (miRNA) mediated regulation of peroxisome proliferator activated receptor alpha (Ppara) in ADPKD. The studies she has proposed have the potential to provide profound new insights on the metabolic reprogramming that occurs in ADPKD. UT Southwestern is a world renowned institution with a proven track record in performing cutting- edge research, providing excellent resources, and training successful young faculty to become leaders in their respective fields. The candidate has developed a comprehensive career development plan to complement her research aims. The candidate's training aims include 1) metabolic phenotyping 2) gene editing and 3) statistics/bioinformatics. Her co-mentors complement each other perfectly to properly guide and monitor the candidate's research experience and training. Dr. Steven Kliewer, a member of the National Academy of Sciences, is a world renowned expert in nuclear hormone receptors and metabolism. Dr. Vishal Patel, Assistant Professor in Nephrology, is an international expert in miRNAs and ADPKD. In addition, Dr. Chao Xing, Associate Professor and Director of the McDermott Bioinformatics Core at UT Southwestern, will serve an advisory role for the applicants training in statistics/bioinformatics. An advisory committee consisting of 4 exemplary scientists and physician scientists will provide additional support and mentorship for career development. The applicant will determine whether preventing miRNAs from binding to the Ppara 3'-UTR enhances its translation, improves oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO), and attenuates cyst growth in ADPKD. She has developed a unique set of tools to precisely address each of her specific aims. Aim 1 will determine whether deletion of miRNA binding sites from Ppara 3'-UTR normalizes its expression and slows cyst growth. Aim 2 will determine whether deletion of miRNA binding sites from Ppara 3'-UTR improves OXPHOS/FAO. Aim 3 will determine whether Ppara 3'-UTR Target Site Blockers can stabilize its expression and slow cyst growth. Together these studies will establish Ppara 3'-UTR as a drug target for ADPKD and provide proof-of-principle for targeted stabilization of mRNA transcripts as a novel therapeutic approach.