The Novel Approach of RNA Based Therapeutic Technologies

基于 RNA 的治疗技术的新方法

基本信息

批准号：
7560006
负责人：
BA-BIE TENG
金额：
$ 37.13万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-01 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7560006
关键词：
Animals Anti-Inflammatory Agents Anti-inflammatory Antiatherogenic Aorta Apolipoproteins B Applications Grants Arterial Fatty Streak Arteries Atherosclerosis Biological Assay Blood Vessels C57BL/6 Mouse Cardiac Cardiovascular system Catalytic Domain Catalytic RNA Cells Cessation of life Cholesterol Cleaved cell Clinical Collaborations Complement Consensus Sequence Coronary Coronary Arteriosclerosis Development Diet Disease Elements Enzymes Esterified Fatty Acids Etiology Event Familial Hypercholesterolemia Gene Expression Genes Genetic Goals Heart Diseases Hepatocyte Human Hydrolysis Hyperlipidemia Hypobetalipoproteinemia In Vitro Inflammation Inflammatory Inflammatory Response Ischemic Stroke Kupffer Cells LDL Cholesterol Lipoproteins Laboratories Lead Length Life Lipids Lipoproteins Long-Term Effects Low Density Lipoprotein oxidation Low-Density Lipoproteins Lysophosphatidylcholines Measures Mediating Messenger RNA Metabolism Modeling Modification Molecular Molecular Conformation Molecular Weight Morbidity - disease rate Mus Nucleotides Operative Surgical Procedures Outcome Study Oxidative Stress Pathway interactions Patients Pharmacotherapy Phospholipase A2 Phospholipids Plasma Prevention Production Property Proteins RB1 gene RNA Risk Site Societies Staging Structure Technology Testing Therapeutic Therapeutic Agents adeno-associated viral vector atherogenesis base cardiovascular risk factor cerebral artery dalton design gene therapy hammerhead ribozyme in vitro Assay in vivo inflammatory marker innovation insight lipid mediator lipoprotein-associated phospholipase A(2)low density lipoprotein inhibitor low density lipoprotein triglyceride mRNA Expression macrophage mortality mouse model novel novel strategies novel therapeutics particle premature atherosclerosis prevent stem vector

项目摘要

DESCRIPTION (provided by applicant): The long-term objectives of this proposal are to design and develop novel strategies for regulating the development and progression of atherosclerosis and to provide new insights into the application of target specific hammerhead ribozymes for inhibiting gene expression. Our ultimate goal will be to develop human gene therapy strategies for alleviating atherosclerosis, which is responsible for most clinical manifestations of coronary artery disease and ischemic stroke. Atherosclerosis is recognized as an inflammatory disease, with the presence of LDL in the intima (subendothelial matrix) leading to inflammatory responses, oxidative stress, and plaque formation. Our laboratory has developed a genetically defined mouse model of atherosclerosis (LDb mice), which has a plasma lipoprotein profile that resembles humans with hyperlipidemia and results in diet-independent atherosclerosis. The etiology of atherosclerosis in this model mimics that of humans. In this application, we plan to develop novel strategies using minimal and tertiary stabilized hammerhead ribozymes to target two genes (apolipoprotein B mRNA and lipoprotein-associated phospholipase A2) simultaneously and will test the effect of this strategy on atherosclerosis development in LDb mice. We hypothesize that inhibiting gene expression of apoB and Lp-PLA2 mRNA will decrease oxidation of LDL, reduce the inflammatory response, and inhibit atherosclerosis development in LDb mice. We will use the double-stranded chimeric adeno-associated viral vector AAV2/8 to deliver these hammerhead ribozyme molecules to mice and will examine the persistence of both vectors and ribozyme gene expression in vivo. This study will allow us to understand the molecular mechanisms used by ribozymes to regulate gene expression and the ability of these ribozymes to inhibit atherosclerosis development. In summary, this study will provide a novel therapeutic treatment for coronary atherosclerosis and provide evidence of the efficiency and efficacy of RNA based molecules as potential therapeutic agents.

描述（由申请人提供）：该提案的长期目标是设计和制定调节动脉粥样硬化的发展和进展的新型策略，并为抑制基因表达的靶标特异性锤头核酶的应用提供新的见解。我们的最终目标是制定人类基因治疗策略来减轻动脉粥样硬化，这是导致大多数冠状动脉疾病和缺血性中风的临床表现。动脉粥样硬化被认为是一种炎症性疾病，内膜（下皮基质）中存在LDL，导致炎症反应，氧化应激和斑块形成。我们的实验室开发了一种遗传定义的动脉粥样硬化小鼠模型（LDB小鼠），该模型具有血浆脂蛋白谱，类似于人类患有高脂血症的人，并导致饮食中无关的动脉粥样硬化。该模型中动脉粥样硬化的病因模仿了人类的病因。在此应用中，我们计划使用最小和三级稳定的锤头核酶制定新的策略，以同时靶向两个基因（载脂蛋白B mRNA和脂蛋白相关的磷脂酶A2），并将测试LDB小鼠中动脉粥样硬化的效果。我们假设抑制APOB和LP-PLA2 mRNA的基因表达将降低LDL的氧化，降低炎症反应，并抑制LDB小鼠的动脉粥样硬化发展。我们将使用双链嵌合腺相关的病毒载体AAV2/8将这些锤头核酶分子传递给小鼠，并将检查载体和核酶基因表达在体内的持久性。这项研究将使我们能够理解核酶用于调节基因表达的分子机制以及这些核酶抑制动脉粥样硬化发育的能力。总而言之，这项研究将为冠状动脉粥样硬化提供新的治疗方法，并提供基于RNA的分子作为潜在治疗剂的效率和功效的证据。