lncRNA Function and Mechanisms during Cardiac Development and Disease

心脏发育和疾病过程中lncRNA的功能和机制

基本信息

批准号：
10608600
负责人：
Da-Zhi Wang
金额：
$ 55.98万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10608600
关键词：
Affect Apoptosis Area Atherosclerosis Biochemical Biological Biological Process Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular Diseases Cardiovascular system Cause of Death Cell Nucleus Cell Proliferation Code Cyclin-Dependent Kinase Inhibitor 3 Data Defect Dependovirus Development Disease Gene Delivery Gene Expression Gene Expression Regulation Genes Genetic Genetic Engineering Genetic Transcription Genome Goals Growth Heart Heart Diseases Heart Hypertrophy Human Hypertrophic Cardiomyopathy Investigation Length Link Medical MicroRNAs Mission Molecular Molecular Target Mus Mutant Strains Mice Myocardial Infarction Natural regeneration Nuclear Protein Nucleotides Organism Pathologic Pathologic Processes Patients Physiological Physiological Processes Play Process Proliferating Proteins RNA Regulation Reporting Research Role Stress TP53 gene Testing Therapeutic Transcript Translating Translational Repression United States United States National Institutes of Health Untranslated RNA Vascular Diseases Vascular remodeling adeno-associated viral vector cardiac regeneration cardiogenesis design differential expression effective therapy epigenetic regulation gain of function gene repression heart function improved in vivo interest ischemic cardiomyopathy knock-down loss of function model design molecular targeted therapies mouse model mutant mouse model new therapeutic target novel novel therapeutic intervention overexpression pressure protein function response screening therapeutic evaluation therapeutic target therapeutically effective transcriptome sequencing

项目摘要

ABSTRACT Cardiovascular disease remains the leading cause of death in the United States; however, the genetic causes and molecular mechanisms underlying these medical conditions have yet to be thoroughly elucidated. As a result, the identification of new therapeutic targets for the effective treatment of these diseases is urgently required. Because the majority of the genome is actively transcribed to produce a vast number of non-coding RNA transcripts, this project is focused on determining the role of long non-coding RNAs in heart disease, which is an understudied and important area of investigation. Thousands of long non-coding RNAs (lncRNAs), which are defined as non-coding RNA transcripts greater than 200 nucleotides in length, have been found to have biological activity in humans and other organisms; they are considered novel regulatory molecules of numerous physiological and pathological processes, including those in the cardiovascular system. Our earlier RNA-seq studies identified many differentially expressed lncRNAs in the hearts of patients with ischemic cardiomyopathy. One of these lncRNAs, known as large intergenic non-coding RNA-p21 (lincRNA-p21), was previously shown to be a transcriptional target of tumor protein p53 and a novel regulator of cell proliferation and apoptosis. More recently, it has been implicated in the control of the regulation of vascular remodeling responses in atherosclerosis. However, the function of lincRNA-p21 in the heart and cardiac disease remains unknown. We propose to examine the function of lincRNA-p21 in hypertrophic cardiomyopathy and cardiac regeneration. Our preliminary data using mutant mouse lines demonstrates that lincRNA-p21 is also involved in cardiac remodeling in response to pathophysiological stress. Therefore, the overall goal of this application is to clearly define the function and molecular mechanisms of lincRNA-p21 in the heart. We propose to do this by pursuing the following Specific Aims: 1) to systematically study the in vivo function of lincRNA-p21 in the heart using gain- and loss-of-function mouse models, 2) to define the molecular mechanisms by which lincRNA- p21 regulates cardiac remodeling by testing the hypothesis that this lncRNA alters cardiac function by affecting the expression and function of Kap1/Trim28-dependent genes, and 3) to examine the therapeutic potential of lincRNA-p21 in treating cardiomyopathy using adeno-associated virus (AAV) vectors to either overexpress, or AAV/gapmers to knockdown this lncRNA, in mice with cardiomyopathy. As a result, this proposal will systematically and rigorously assess the role of lincRNA-p21 in heart disease and establish the molecular mechanisms underlying the function of this intriguing lncRNA. The information obtained from these studies are anticipated to identify important new molecular targets for the therapeutic treatment of cardiac disease.

抽象的心血管疾病仍然是美国死亡的主要原因。但是，遗传原因这些医疗状况的基础机制和分子机制尚未彻底阐明。因此，迫切需要确定有效治疗这些疾病的新治疗靶标。因为大多数基因组被积极转录以产生大量的非编码RNA 笔录，该项目的重点是确定长期非编码RNA在心脏病中的作用，这是一个研究且重要的调查领域。成千上万的非编码RNA（LNCRNA），已定义为长度大于200核苷酸的非编码RNA转录本具有生物学人类和其他生物的活动；它们被认为是众多新型调节分子生理和病理过程，包括心血管系统中的过程。我们较早的RNA-Seq 研究确定了缺血性心肌病患者心脏中许多差异表达的LNCRNA。这些LNCRNA之一，称为大型非编码RNA-P21（LincRNA-P21），以前已显示为是肿瘤蛋白p53的转录靶标，也是细胞增殖和凋亡的新调节剂。更多的最近，它与控制血管重塑反应的调节有关动脉粥样硬化。但是，Lincrna-P21在心脏和心脏病中的功能仍然未知。我们建议检查Lincrna-P21在肥厚性心肌病和心脏的功能再生。我们使用突变小鼠系的初步数据表明，Lincrna-P21也参与了对病理生理应激的响应心脏重塑。因此，此应用程序的总体目标是清楚地定义了Lincrna-P21在心脏中的功能和分子机制。我们建议这样做追求以下具体目的：1）系统地研究lincrna-p21的体内功能使用功能障碍小鼠模型的心脏，2）定义lincrna-的分子机制 P21通过测试该LNCRNA通过影响心脏功能的假设来调节心脏重塑 KAP1/TRIM28依赖性基因的表达和功能，以及3）检查的治疗潜力 LincRNA-P21使用腺相关病毒（AAV）向量进行过表达或在患有心肌病的小鼠中，AAV/Gapmers敲除了这种lncRNA。结果，该建议将系统，严格地评估Lincrna-P21在心脏病中的作用并建立分子该有趣的lncRNA功能的基础机制。从这些研究中获得的信息是预计将确定重要的新分子靶标，以治疗心脏病的治疗。