Novel Modular Vascular Patterning Assay for HTS

HTS 的新型模块化血管模式分析

• 批准号: 7648164
• 负责人: ROYCE MOHAN
• 金额: $ 29.56万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7648164
• 关键词: 3-Dimensional; Address; Adoption; Age related macular degeneration; Arthritis; Biological; Biological Assay; Biology; Blood Vessels; Cardiovascular Diseases; Cell Line; Characteristics; Chemicals; Complex; Computer software; Controlled Study; Development; Diabetes Mellitus; Differentiation and Growth; Disease; Diversity Library; Endothelial Cells; FDA approved; Funding; Goals; Grant; Growth; Growth Factor; Hand; Health; Heart Diseases; Homeostasis; Human; Hyperglycemia; Hypoxia; Image; Image Analysis; Impaired wound healing; Individual; Inflammatory; Lead; Life; Malignant Neoplasms; Manuals; Mind; Modeling; Multicellular Process; Multiple Organ Failure; Optics; Pathway interactions; Pattern; Pharmaceutical Preparations; Preclinical Drug Evaluation; Principal Investigator; Process; Production; Quality Control; Research; Robotics; Running; Screening procedure; Signal Transduction; Simulate; Site; Stimulus; Stroke; System; Technology; Therapeutic; United States National Institutes of Health; Validation; Vascular Endothelial Cell; Wound Healing; angiogenesis; drug discovery; high throughput screening; human disease; improved; innovation; novel; programs; protein function; prototype; response; small molecule libraries; tool; 3-Dimensional; Address; Adoption; Age related macular degeneration; Arthritis; Biological; Biological Assay; Biology; Blood Vessels; Cardiovascular Diseases; Cell Line; Characteristics; Chemicals; Complex; Computer software; Controlled Study; Development; Diabetes Mellitus; Differentiation and Growth; Disease; Diversity Library; Endothelial Cells; FDA approved; Funding; Goals; Grant; Growth; Growth Factor; Hand; Health; Heart Diseases; Homeostasis; Human; Hyperglycemia; Hypoxia; Image; Image Analysis; Impaired wound healing; Individual; Inflammatory; Lead; Life; Malignant Neoplasms; Manuals; Mind; Modeling; Multicellular Process; Multiple Organ Failure; Optics; Pathway interactions; Pattern; Pharmaceutical Preparations; Preclinical Drug Evaluation; Principal Investigator; Process; Production; Quality Control; Research; Robotics; Running; Screening procedure; Signal Transduction; Simulate; Site; Stimulus; Stroke; System; Technology; Therapeutic; United States National Institutes of Health; Validation; Vascular Endothelial Cell; Wound Healing; angiogenesis; drug discovery; high throughput screening; human disease; improved; innovation; novel; programs; protein function; prototype; response; small molecule libraries; tool

DESCRIPTION (provided by applicant): The vascular endothelial cells lining blood vessels in humans are one of the principle sites that become involved in inflammatory and proliferative responses to a diverse array of human diseases. Microvascular homeostasis is thus a vital component of human health; its inappropriate activation in response to inflammatory and angiogenic stimuli can become a pathogenic component fueling the growth and spread of cancers, and contributing to debilitating arthritis, age-related macular degeneration and multiple organ failure associated with underlying diseases such as diabetes. On the other hand, impaired angiogenesis is also equally pathogenic, and afflicts its victims by slowing down wound healing and contributing to heart diseases and stroke. Collectively, given the complexity of the angiogenesis signaling system, these major burdens of human health that arise from dysregulation of blood vessel growth need to be addressed by a more concerted effort in drug discovery. Biological assays that model the processes of angiogenic diseases can assist the process of drug discovery and disease target identification. However, currently few assays represent the complexity of the diseased microvasculature as they typically focus on one pathogenic mechanism/pathway. With this in mind, we propose to continue the development of a high content high throughput screening (HC-HTS) vascular patterning assay, which we have recently validated as drug screening tool through a previously funded NIH Roadmap Initiative R21 grant. In this R01 proposal, we plan to extend the scale and scope of the three dimensional endothelial cell sprouting assay (3D-ECSA) to promote its adoption for the HTS paradigm. Our innovative approaches bring in 1) modern automated robotic systems that allow us to improve efficiency and standardize production of spheroids, 2) high content image analysis software to use with 3D-ECSA under HTS conditions, and 3) development of a pilot scale chemical library focused on the immunoproteosome as a chemical enabling tool towards validation of the 3D-ECSA. The successful accomplishments of these goals will not only afford us a valuable tool for large scale biology, but will help bring forward a technology advancement to identify new classes of chemical probes of protein function and drug leads for life saving therapeutics.