Genome-wide profiling of human vascular response to oxidized lipoprotreins

人类血管对氧化脂蛋白反应的全基因组分析

• 批准号: 7908422
• 负责人: Brett R Blackman
• 金额: $ 16.68万
• 依托单位: HEMOSHEAR THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7908422
• 关键词: Agreement; Algorithms; Anatomy; Animal Model; Arteries; Atherosclerosis; Bioinformatics; Biological; Biological Assay; Biological Markers; Biomimetic Devices; Biotechnology; Blood Vessels; Cardiovascular Agents; Cardiovascular system; Cell Culture Techniques; Cell Differentiation process; Cells; Clinical Trials; Coculture Techniques; Custom; Data; Data Set; Databases; Detection; Development; Devices; Differentiation Antigens; Disease; Dose; Endothelial Cells; Environment; Environmental Risk Factor; Exhibits; Expenditure; Exposure to; Fostering; Gene Expression; Genes; Genetic Transcription; Genomics; Harvest; Hour; Human; Human Genome; Inflammatory; Informatics; Investigation; Lead; Lipoproteins; Low-Density Lipoproteins; Maps; Marketing; Mediating; Mission; Modeling; Molecular; Molecular Profiling; Molecular Target; National Heart, Lung, and Blood Institute; Ontology; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Phase; Phenotype; Prevention; Quality Control; RNA; Regulator Genes; Relative (related person); Research; Risk Factors; Role; Safety; Sampling; Scheme; Screening procedure; Small Business Innovation Research Grant; Smooth Muscle Myocytes; Staging; Systems Analysis; Systems Biology; Technology; Testing; Therapeutic Intervention; Time; United States; Vascular Diseases; atherogenesis; atheroprotective; base; cardiovascular risk factor; cell type; chemokine; comparison group; cytokine; design; drug development; drug efficacy; genome-wide; hemodynamics; innovation; insight; macrophage; mortality; myocardin; novel; oxidized low density lipoprotein; pre-clinical; programs; public health relevance; research and development; response; success; trend

DESCRIPTION (provided by applicant): Atherosclerosis is a vascular inflammatory disease characterized by dramatic changes in endothelial cell (EC) and smooth muscle cell (SMC) phenotypes. The progression of atherosclerosis is dependent on interactions between vascular cells (EC/SMC), regional hemodynamic flow patterns, and environmental factors such as oxidized lipoprotein species. In line with the Mission of the NHLBI SBIR/STTR program, HemoShear's proposal will foster research on pharmaceuticals, biologics, informatics, and biotechnologies for the causes, prevention, and treatment of blood vessel disorders. Hemoshear has developed a human vascular surrogate device that uniquely mimics the vascular anatomy and hemodynamic environment during the early stages of atherosclerosis. This device enables investigation of the cellular and molecular mechanisms of human atherosclerosis and the identification of novel biomarkers and transcriptional pathways for development of drug therapies. Such cell-based biomimetic devices are being used increasingly during drug development to provide more accurate predictions of human responses than traditional cell-culture assays or animal models. The objective of this proposal is to develop a database that profiles the human vascular response (EC/SMC) to oxidized low density lipoprotein (oxLDL), which has a widely recognized role in the progression of atherosclerosis. Specifically, HemoShear will use high throughput gene arrays to determine the genome-wide profile of EC/SMC gene expression in the presence of oxLDL in the vascular surrogate model. Additionally, HemoShear will use network and pathway analyses to rigorously analyze the gene array results and identify the most oxLDL- responsive transcriptional networks. Taken together, the gene profiles and bioinformatics analyses will comprise a comprehensive genomic database that will reveal the most relevant molecular targets for therapeutic intervention of oxLDL-mediated atherosclerosis. The insight into the cellular/molecular mechanisms of atherosclerosis provided by the genomic database will serve as a basis for developing an innovative, late-stage atherosclerosis device that integrates the presence of oxLDL and macrophages into the current design (Phase II SBIR). PUBLIC HEALTH RELEVANCE: Major challenges in drug development (e.g., efficacy and safety) are due to limited pre-clinical tests that can predict human response to a drug in clinical trials. HemoShear has developed a human vascular surrogate technology for pre-clinical biodiscovery and drug efficacy/safety screening. Atherosclerosis is a blood vessel disorder responsible for more that 40% of all mortality in the United States and an estimated $9 billion in global R&D expenditures spent annually, with few new drugs entering the market. This Phase I SBIR application proposes to further develop our platform technology into a model that better represents the onset of atherosclerosis in arteries, allowing drug companies to identify new targets and test compounds for cardiovascular efficacy/safety.

描述（申请人提供）：动脉粥样硬化是一种血管炎症性疾病，其特征是内皮细胞（EC）和平滑肌细胞（SMC）表型的显着变化。动脉粥样硬化的进展取决于血管细胞 (EC/SMC)、局部血流动力学模式和氧化脂蛋白等环境因素之间的相互作用。根据 NHLBI SBIR/STTR 计划的使命，HemoShear 的提案将促进药物、生物制品、信息学和生物技术的研究，以了解血管疾病的病因、预防和治疗。 Hemoshear 开发了一种人体血管替代装置，能够独特地模拟动脉粥样硬化早期阶段的血管解剖结构和血流动力学环境。该设备能够研究人类动脉粥样硬化的细胞和分子机制，并识别新的生物标志物和转录途径，以开发药物疗法。这种基于细胞的仿生装置在药物开发过程中得到越来越多的使用，以提供比传统细胞培养测定或动物模型更准确的人类反应预测。该提案的目的是开发一个数据库，描述人类血管对氧化低密度脂蛋白（oxLDL）的反应（EC/SMC），氧化低密度脂蛋白在动脉粥样硬化的进展中具有广泛认可的作用。具体来说，HemoShear 将使用高通量基因阵列来确定血管替代模型中存在 oxLDL 时 EC/SMC 基因表达的全基因组谱。此外，HemoShear 将使用网络和通路分析来严格分析基因阵列结果，并确定对 oxLDL 反应最强的转录网络。总而言之，基因谱和生物信息学分析将构成一个全面的基因组数据库，该数据库将揭示 oxLDL 介导的动脉粥样硬化治疗干预最相关的分子靶点。基因组数据库提供的对动脉粥样硬化细胞/分子机制的深入了解将作为开发创新的晚期动脉粥样硬化装置的基础，该装置将 oxLDL 和巨噬细胞的存在整合到当前的设计中（II 期 SBIR）。 公共卫生相关性：药物开发中的主要挑战（例如功效和安全性）是由于可以预测人类对临床试验中药物反应的临床前测试有限。 HemoShear 开发了一种用于临床前生物发现和药物功效/安全性筛选的人体血管替代技术。动脉粥样硬化是一种血管疾病，占美国所有死亡率的 40% 以上，全球每年的研发支出估计为 90 亿美元，但很少有新药进入市场。这一 I 期 SBIR 申请旨在进一步将我们的平台技术开发成一个模型，更好地代表动脉粥样硬化的发生，使制药公司能够确定新的靶点并测试化合物的心血管功效/安全性。