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.

项目摘要该提案的总体目的是为Ronak博士提供严格的研究和培训经验。拉基亚成为一名独立的医师科学家。申请人是董事会认证的肾脏科医生最近在一个独立资助的实验室中担任NIH-T32研究员，完成了博士后培训。她计划提高她的技能并以自己的经验为基础，成为一名出色的医师科学家和全国公认的常染色体显性多囊肾脏疾病（ADPKD）和代谢专家。这该提案的目标旨在提供新的科学见解，并允许申请人成长和通过适当的指导达到她的全部潜力。她将研究破坏microRNA（miRNA）的影响 ADPKD中介导的过氧化物酶体增殖物激活受体α（PPARA）的调节。她的研究提出的有可能对发生的代谢重编程提供深刻的新见解在ADPKD中。 UT Southwestern是一个世界知名机构边缘研究，提供优质的资源以及培训成功的年轻教师，成为他们的领导者各个领域。候选人制定了一项全面的职业发展计划，以补充她研究目的。候选人的培训目的包括1）代谢表型2）基因编辑和3）统计/生物信息学。她的副官员互相补充，以正确指导和监视候选人的研究经验和培训。史蒂文·克莱尔（Steven Kliewer）博士，美国国家学院的成员科学是世界著名的核激素受体和代谢专家。 Vishal Patel博士，肾脏学助理教授是MiRNA和ADPKD的国际专家。此外，Chao博士 Xing是UT Southwestern的McDermott BioInformatics Core的副教授兼主任，将服务申请人在统计/生物信息学方面培训的咨询角色。一个由4个组成的咨询委员会典型的科学家和医师科学家将为职业提供额外的支持和指导发展。申请人将确定是否防止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），并改善减弱ADPKD中囊肿的生长。她开发了一套独特的工具来精确解决她的每个工具具体目标。 AIM 1将确定miRNA结合位点的缺失是否从PPARA 3'-UTR归一化表达并减慢囊肿的生长。 AIM 2将确定miRNA结合位点是否从PPARA中删除 3'-UTR改善了Oxphos/fao。 AIM 3将确定PPARA 3'-UTR目标站点阻滞剂是否可以稳定其表达并缓慢的囊肿生长。这些研究共同将PPARA 3'-UTR作为药物建立 ADPKD的目标，并提供原则证明mRNA转录本作为新颖的靶向稳定治疗方法。