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Optical Tools to Assess the Role of Cardiac Function in the Development of Congenital Heart Defects

评估心脏功能在先天性心脏缺陷发展中的作用的光学工具

基本信息

批准号：
10211096
负责人：
MICHAEL W. JENKINS
金额：
$ 76.74万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10211096
关键词：
3-Dimensional Affect Algorithms Area Betaine Biological Process Blood flow Cardiac Cardiovascular Diseases Cell Shape Cells Cohort Studies Computer software Congenital Heart Defects Data Development DiGeorge Syndrome Diffusion Disease Disease model Early Diagnosis Embryo Embryonic Heart Fetal Alcohol Exposure Fetal Alcohol Spectrum Disorder Fluorescent in Situ Hybridization Funding Gene Expression Gene Expression Profile Genetic Glutathione Heart Histology Image Imaging Device Immunohistochemistry In Situ Knowledge Lead Link Malignant Neoplasms Maps Measurement Measures Mechanical Stress Methods Modeling Molecular Morbidity - disease rate Morphology Optical Coherence Tomography Optics Pathway interactions Pattern Play Positioning Attribute Prevention Protocols documentation Quail RNA Reporting Role Sequencing By Hybridizations Shprintzen syndrome Signal Transduction Specificity Structure System Testing Tissues Tube Work addiction cardiogenesis cell type deep learning detection method experience experimental study heart function hemodynamics image processing improved in situ sequencing indexing nervous system disorder novel optical imaging prevent shear stress statistics tool virtual

项目摘要

Project Summary We and others have shown that altered hemodynamics and shear stress can lead to congenital heart defects (CHDs), but still there is limited information on how these forces affect molecular signaling. Studying the impact of abnormal hemodynamics and shear stress becomes even more urgent when we consider that perturbed blood flow may be a contributing factor to a large percentage of CHDs regardless of whether the initial trigger is environmental or genetic. Although our group and others have recently developed extremely useful optical imaging tools (e.g., optical coherence tomography – OCT) to assess hemodynamics and shear stress, and connected these measurements to CHDs, it has been difficult to link shear stress with the affected molecular pathways. Our group and others have performed qPCR experiments on control and shear-stress perturbed hearts to see how abnormal hemodynamics alters gene expression. However, this approach requires the entire embryonic heart for one measurement, missing all spatial and cell-type information, particularly at the endocardial layer. In order to successfully assess how shear stress affects molecular signaling throughout the looping heart, we need to improve upon our OCT methods, develop 3D methods for assessing embryonic heart gene expression, and create an advanced image processing pipeline to analyze data and relate regional shear stress to gene expression. This renewal proposal will continue our work developing tools that can lead to a more sophisticated understanding of how cardiac function (e.g., hemodynamics and electrical impulse conduction) affects heart development, enabling potential therapies to avoid or mitigate CHDs. In this proposal, we will focus on developing tools to understand how oscillatory shear stress (quantified as oscillatory shear index - OSI) influences gene expression and leads to CHDs. In our preliminary studies, we increased regurgitant blood flow (causing increased OSI) to show that alterations to OSI leads to smaller cardiac cushions (valve precursors) and ultimately, to CHDs. Increased regurgitant blood flow and smaller cushions is present in our two disease models (fetal alcohol spectrum disorders – FASD; velo-cardio-facial syndrome/Digeorge) and our FASD prevention compounds partially normalize blood flow, cardiac cushion size, and greatly reduce morbidity and CHDs. Our specific aims include 1) advance our OCT system and shear stress analysis, 2) develop fluorescence in situ hybridization (FISH) protocols to measure gene expression in 3D, 3) develop an image processing pipeline to relate gene expression to shear stress, and 4) determine the impact of shear stress on gene expression. Upon completion, we will have significantly more information on how shear stress affects molecular expression. With this knowledge, we will be better equipped to determine which molecular pathways are most influenced by altered hemodynamics, to develop earlier detection methods and potentially develop strategies to prevent CHDs more effectively.

项目总结