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

过氧化物酶体增殖物激活受体α在常染色体显性多囊肾病中的作用

基本信息

批准号：
10397035
负责人：
Ronak Lakhia
金额：
$ 15.98万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10397035
关键词：
3&apos Untranslated Regions Address Advisory Committees Affect Agonist Alleles Attenuated Autosomal Dominant Polycystic Kidney Binding Binding Sites Bioinformatics Biological Biological Assay CRISPR/Cas technology Cell Line Complement Consumption Creatinine Cyst Cystic kidney Development Development Plans Disease Progression Disease model Down-Regulation Drug Targeting Epithelial Cells Epithelial cyst FDA approved Faculty Fenofibrate Funding Future Genes Genetic Genus Hippocampus Growth Human Impairment Inherited Institution International Kidney Failure Knowledge Laboratories Malignant Neoplasms Mediating Mentors Mentorship Messenger RNA Metabolic Metabolism MicroRNAs Mitochondria Monitor Mus Mutant Strains Mice Nephrology Nuclear Hormone Receptors Oligonucleotides Oxidative Phosphorylation PPAR alpha Pathogenicity Pathway interactions Patients Pharmacologic Substance Pharmacology Physicians Publishing RNA Regulation Research Research Personnel Research Training Resources Role Scientist Serum Site Structure Testing Therapeutic Time Training Transcript Translational Repression Translations Triolein United States National Academy of Sciences United States National Institutes of Health Work base career development design drug development experience fatty acid oxidation hormone metabolism improved in vivo insight kidney epithelial cell kidney metabolism member metabolic phenotype mid-career faculty mouse model new therapeutic target novel novel therapeutic intervention post gamma-globulins post-doctoral training prevent professor statistics tool transcription factor

项目摘要

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.

项目概要该提案的总体目标是为 Ronak 博士提供严格的研究和培训经验拉希亚成为一名独立的医师科学家。申请人是经过委员会认证的肾脏病专家最近作为 NIH-T32 研究员在一个独立资助的实验室完成了博士后培训。她计划增强她的技能并利用她的经验成为一名优秀的医师科学家和全国公认的常染色体显性多囊肾病 (ADPKD) 和代谢专家。这该提案的目标旨在提出新的科学见解，并使申请人能够成长和发展通过适当的指导充分发挥她的潜力。她将研究破坏 microRNA (miRNA) 的影响 ADPKD 中过氧化物酶体增殖物激活受体 α (Ppara) 的介导调节。她所学的提出有可能为发生的代谢重编程提供深刻的新见解在 ADPKD 中。 UT Southwestern 是一所世界知名的机构，在切割方面拥有良好的记录前沿研究，提供优质资源，并培训成功的年轻教师成为各自领域的领导者各自的领域。该候选人制定了全面的职业发展计划来补充她的不足研究目的。候选人的培训目标包括 1) 代谢表型分析 2) 基因编辑 3) 统计学/生物信息学。她的共同导师完美地互补，以正确地指导和监督候选人的研究经验和培训。 Steven Kliewer 博士，美国国家科学院院士科学界著名的核激素受体和代谢专家。维沙尔·帕特尔博士，肾病学助理教授，是 miRNA 和 ADPKD 领域的国际专家。此外，赵博士德克萨斯大学西南医学中心副教授兼麦克德莫特生物信息学核心主任 Xing 将担任为申请人提供统计/生物信息学培训的咨询服务。顾问委员会由 4 人组成模范科学家和医师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)，以及减弱 ADPKD 中的囊肿生长。她开发了一套独特的工具来精确解决她的每个问题具体目标。目标 1 将确定从 Ppara 3'-UTR 中删除 miRNA 结合位点是否使其正常化表达并减缓囊肿生长。目标 2 将确定是否从 Ppara 中删除 miRNA 结合位点 3'-UTR 改善 OXPHOS/FAO。目标 3 将确定 Ppara 3'-UTR 目标位点阻断剂是否可以稳定其表达并减缓囊肿生长。这些研究将共同确定 Ppara 3'-UTR 作为药物 ADPKD 的靶标，并为 mRNA 转录物的靶向稳定作为一种新型药物提供原理证明治疗方法。