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（由申请人提供）：动脉粥样硬化是一种血管炎性疾病，其特征是内皮细胞（EC）和平滑肌细胞（SMC）表型的急剧变化。动脉粥样硬化的进展取决于血管细胞（EC/SMC）之间的相互作用，区域血流动力学流动模式和氧化脂蛋白种类等环境因素。根据NHLBI SBIR/STTR计划的任务，Hemoshear的提议将促进有关药物，预防和治疗血管疾病的药物，生物制剂，信息学和生物技术的研究。 Hemoshear开发了一种人类血管替代装置，该装置在动脉粥样硬化的早期阶段独特地模仿血管解剖学和血液动力学环境。该设备可以研究人动脉粥样硬化的细胞和分子机制，并鉴定出新型生物标志物和用于开发药物疗法的转录途径。在药物开发过程中，这种基于细胞的仿生装置比传统的细胞培养测定法或动物模型更准确地预测人类反应的预测。该提案的目的是开发一个数据库，该数据库介绍了人类血管反应（EC/SMC）氧化的低密度脂蛋白（OXLDL），该数据库在动脉粥样硬化的进展中具有广泛认可的作用。具体而言，Hemoshear将使用高吞吐量基因阵列来确定在血管替代模型中OXLDL存在下EC/SMC基因表达的全基因组谱。此外，Heamshear将使用网络和途径分析来严格分析基因阵列结果并确定最响应的转录网络。综上所述，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的最相关的分子靶标。基因组数据库提供的动脉粥样硬化的细胞/分子机制的洞察力将作为开发创新的，晚期动脉粥样硬化装置的基础，该基础将OXLDL和巨噬细胞的存在整合到当前设计中（II期SBIR）。 公共卫生相关性：药物开发的主要挑战（例如疗效和安全性）是由于临床前测试有限，可以预测人类对临床试验中药物的反应。 Hemoshear开发了一种人类血管替代技术，用于临床前生物发现和药物疗效/安全筛查。动脉粥样硬化是一种血管疾病，造成全球所有死亡率的40％，估计每年花费的全球研发支出为90亿美元，很少有新药进入市场。此阶段I SBIR应用建议将我们的平台技术进一步发展为一个更好地代表动脉动脉粥样硬化发作的模型，从而使制药公司能够确定新的靶标和测试化合物，以实现心血管疗效/安全性。