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).
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.
| Zhou, Guangjin; Hamik, Anne; Nayak, Lalitha et al. (2012) Endothelial Kruppel-like factor 4 protects against atherothrombosis in mice. J Clin Invest 122:4727-31 |
