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

项目摘要 这项提议的总体目标是为罗纳克博士提供严格的研究和培训经验 拉希亚将成为一名独立的内科科学家。申请人是一名经董事会认证的肾脏科医生 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 计划增强她的技能，并以她的经验为基础，成为一名优秀的内科科学家和 国家公认的常染色体显性遗传性多囊肾病(ADPKD)和代谢方面的专家。这个 本提案的目标旨在提出新的科学见解，并允许申请者成长和 通过适当的指导，充分发挥她的潜力。她将研究破坏微核糖核酸(MiRNA)的效果。 过氧化物酶体增殖物激活受体α(PparA)对ADPKD的调节她的研究 提出有可能对发生的新陈代谢重新编程提供深刻的新见解 在ADPKD。德克萨斯大学西南分校是一家世界知名的机构，在表演切割方面有着良好的记录。 前沿研究，提供优秀资源，培养成功的年轻教员成为其 各自的字段。应聘者已经制定了一个全面的职业发展计划来补充她的不足 研究目的。应聘者的培训目标包括1)代谢表型2)基因编辑和3) 统计学/生物信息学。她的合作导师完美地互补，适当地指导和监督 应聘者的研究经验和培训。史蒂文·克利维尔博士，美国国家科学院院士 是世界著名的核激素受体和新陈代谢专家。维沙尔·帕特尔博士 肾病学助理教授，是miRNAs和ADPKD方面的国际专家。此外，赵博士 Xing，德克萨斯大学西南分校麦克德莫特生物信息学核心副教授兼主任，将担任 为接受统计/生物信息学培训的申请者提供咨询服务。由4人组成的咨询委员会 模范科学家和内科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miRNAs与Ppar3‘-Utr结合 加强其翻译，改善氧化磷酸化(OXPHOS)和脂肪酸氧化(FAO)，以及 抑制ADPKD的囊性生长。她开发了一套独特的工具来精确地解决她的每一个人 明确的目标。目标1将确定从Ppara3‘-UTR中删除miRNA结合位点是否使其正常化 表达，并减缓囊泡的生长。AIM 2将确定是否删除Ppara中的miRNA结合位点 3‘-UTR改进了OXPHOS/FAO。AIM 3将确定PPara3‘-UTR靶点阻滞剂是否可以 稳定其表达，减缓包囊生长。这些研究将使PPAR3‘-UTR成为一种药物 作为一种新的靶向靶向ADPKD并为靶向稳定mRNA转录物提供原理证明 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.