Genome-wide profiling of human vascular response to oxidized lipoprotreins

描述（由申请方提供）：动脉粥样硬化是一种血管炎性疾病，其特征为内皮细胞（EC）和平滑肌细胞（SMC）表型的显著变化。动脉粥样硬化的进展取决于血管细胞（EC/SMC）、局部血流动力学流动模式和环境因素（如氧化脂蛋白）之间的相互作用。根据NHLBI SBIR/STTR计划的使命，HemoShear的提案将促进对药物、生物制剂、信息学和生物技术的研究，以用于血管疾病的病因、预防和治疗。Hemoshear开发了一种人体血管替代器械，可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，用于开发药物疗法。这种基于细胞的仿生装置在药物开发过程中越来越多地使用，以提供比传统细胞培养试验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，该数据库描述了人体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公认的作用。具体而言，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将使用网络和途径分析来严格分析基因阵列结果，并确定最oxLDL响应的转录网络。总之，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，揭示oxLDL介导的动脉粥样硬化治疗干预的最相关分子靶点。对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（第二阶段SBIR）。 公共卫生相关性： 药物开发的主要挑战（例如，有效性和安全性）是由于有限的临床前测试，其可以预测临床试验中人类对药物的反应。HemoShear开发了一种用于临床前生物发现和药物疗效/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，估计每年全球研发支出为90亿美元，几乎没有新药进入市场。SBIR的第一阶段申请旨在将我们的平台技术进一步开发成一种模型，更好地代表动脉粥样硬化的发作，使制药公司能够确定新的靶点和测试化合物的心血管疗效/安全性。

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.