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

• 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
• 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

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.

摘要 心血管疾病仍然是美国死亡的主要原因;然而， 并且这些医学病症的分子机制尚未被彻底阐明。因此，在本发明中， 迫切需要鉴定有效治疗这些疾病的新的治疗靶点。 因为基因组的大部分被活跃地转录以产生大量的非编码RNA 转录本，这个项目的重点是确定长的非编码RNA在心脏病中的作用，这是一个 未被充分研究的重要领域成千上万的长非编码RNA（lncRNA）， 定义为长度大于200个核苷酸的非编码RNA转录物，已经发现具有生物学活性。 活性在人类和其他生物体;他们被认为是新的调节分子的许多 生理和病理过程，包括心血管系统中的过程。我们早期的RNA-seq 研究鉴定了缺血性心肌病患者心脏中许多差异表达的lncRNA。 其中一种lncRNA被称为大基因间非编码RNA-p21（lincRNA-p21），此前已被证明可以 是肿瘤蛋白p53的转录靶点，是细胞增殖和凋亡的新调节因子。更 最近，它已被牵连在血管重塑反应的调节的控制中， 动脉粥样硬化然而，lincRNA-p21在心脏和心脏疾病中的功能仍然未知。 我们建议检测lincRNA-p21在肥厚型心肌病和心脏病中的功能， 再生我们使用突变小鼠系的初步数据表明，lincRNA-p21也参与了 病理生理应激后的心脏重塑。因此，本申请的总体目标是 明确定义lincRNA-p21在心脏中的功能和分子机制。我们建议采取以下措施 本研究的具体目的如下：1）系统地研究lincRNA-p21在肿瘤细胞中的体内功能， 心脏使用获得和丧失功能的小鼠模型，2）定义lincRNA- p21调节心脏重塑，通过检验这一假设，即这种lncRNA改变心脏功能， Kap 1/Trim 28依赖基因的表达和功能，以及3）检查Kap 1/Trim 28依赖基因的治疗潜力。 lincRNA-p21在使用腺相关病毒（AAV）载体治疗心肌病中的过度表达，或 AAV/gapmers敲低这种lncRNA，在心肌病小鼠中。因此，该提案将 系统和严格地评估lincRNA-p21在心脏病中的作用，并建立分子生物学模型。 这种有趣的lncRNA的功能机制。从这些研究中获得的信息是 预计将确定用于心脏病治疗的重要新分子靶点。