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A scalable optogenetic system of focal stroke induction in zebrafish for testing stroke disparity genes

用于测试中风差异基因的斑马鱼局灶性中风诱导的可扩展光遗传学系统

基本信息

批准号：
10359724
负责人：
Ju-Ahng Lee
金额：
$ 11.1万
依托单位：
NORTH CAROLINA CENTRAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-07 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10359724
关键词：
3D Print Adopted Adult Affect African African American population African ancestry Alteplase Animal Model Animals Apolipoproteins Apoptotic Biological Models Black Populations Blood Circulation Blood Vessels Brain Brain hemorrhage Caucasians Cause of Death Cell Death Cerebrum Chemicals Chimeric Proteins Chronic Kidney Failure Data Drug Screening Effectiveness Embryo Endothelial Cells Endothelium FDA approved Frequencies Genes Genetic Heart Hemorrhage Human Incidence Individual Infarction Injections Injury Ischemic Stroke Kidney Diseases Light Lighting Location Manuals Measures Medicine Methods Middle Cerebral Artery Occlusion Modeling Mus Nature Operative Surgical Procedures Pathology Persons Pharmaceutical Preparations Photosensitivity Photosensitizing Agents Platelet aggregation Predisposition Procedures Reproducibility Research Rest Risk Risk Factors Rodent Rose Bengal Rupture Severities Stroke System Testing Therapeutic Transgenic Organisms Variant Vertebrates Zebrafish behavior test cerebral artery cranium design disability genetic approach genetic variant genome wide association study mortality novel novel strategies novel therapeutics optogenetics post stroke risk variant scale up stroke incidence stroke model stroke risk zebrafish development

项目摘要

PROJECT SUMMARY/ABSTRACT Stroke is one of the leading causes of death in the U.S. and also a leading cause of adult disability with severe societal burdens. Ischemic strokes, caused by the thromboembolic occlusion of cerebral arteries, constitute the majority of stroke incidences and the rest are hemorrhagic strokes with ruptured blood vessels. In the U.S., stroke incidence shows clear disparity between African Americans and Caucasians with much higher frequency (~240%) in blacks. Despite intensive search for treatment, recombinant tissue plasminogen activator (rtPA) remains the only FDA-approved post-stroke medicine with limited effectiveness. Behind this woefully inadequate dearth of stroke therapeutics lies the difficulties in generating a sufficiently large number of stroke-induced animals for effective drug screening, as a highly labor-intensive surgical procedure (middle cerebral artery occlusion) is still the method of choice to induce ischemic strokes in model animals. Photothrombosis is one of rapidly adopted new methods to induce ischemic strokes in rodents, with a number of advantages such as highly reproducible infarct size and location with minimal mortality. In this procedure, focal illumination of defined wavelength light on the exposed skull activates an IV-injected photosensitive chemical (eg. Rose-Bengal) in the bloodstream, causing injuries in endothelial cells and local platelet aggregation, leading to the clogging of the affected blood vessel. However, even in this case labor-intensive procedures that cannot not easily be scaled up must be utilized to create the stroke model. Recently, photothrombic ischemic stroke has also been successfully induced in the adult zebrafish brain by focal illumination following a manual injection of Rose-Bengal, thus providing an additional vertebrate animal model system for stroke research. In this regard, an exciting novel genetic approach, which eliminates the manual injection of photosensitive chemicals, was recently created and tested successfully to selectively induce apoptotic cell death by light illumination in the adult zebrafish heart. Here we propose a creation of a readily scalable, optogenetically induced stroke system using transgenic zebrafish, development of a behavioral test system to identify novel therapeutic chemicals, and to test GWAS (genome wide association study)-identified stroke risk variants of the human APOL1 gene, also known as prominent kidney disorder risk factors in people of African ancestry.

项目总结/文摘