The morphogenetic regulation of cardiac valves by fluid flow.

流体流动对心脏瓣膜的形态发生调节。

• 批准号: 7321799
• 负责人: JAY D POTTS
• 金额: $ 10.04万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7321799
• 关键词: 3-Dimensional; Affect; Atomic Force Microscopy; Biochemical; Biological; Biological Assay; Biological Models; Biomedical Engineering; Cardiac; Cardiac conduction system; Cardiovascular system; Cells; Collagen; Complex; Condition; Congenital Abnormality; Congenital Heart Defects; Data; Development; Environment; Event; Exposure to; Extracellular Matrix Proteins; Funding; Gene Expression; Gene Expression Regulation; Genes; Goals; Grant; Heart; Heart Valves; Independent Scientist Award; Knockout Mice; Knowledge; Laboratories; Mechanics; Methods; Modeling; Molecular; Monitor; Morphogenesis; Morphology; Mus; Numbers; Pathway interactions; Personal Satisfaction; Play; Principal Investigator; Process; Property; Range; Regulation; Research; Research Personnel; Rheology; Role; Signal Pathway; Signal Transduction; Staging; Structural Protein; System; Techniques; Testing; Time; Tissue Engineering; Tissues; Tube; abstracting; congenital heart disorder; design; fluid flow; gene therapy; intracellular protein transport; programs; protein expression; protein localization location; research study; response; scaffold

DESCRIPTION (provided by applicant): The goal of this KO2 proposal is to allow the Principal Investigator to understand the role that fluid flow has on regulating key gene that control the morphology of developing heart valves, providing him with greater than 75% of time dedicated to his research over the next five years. Fluid flow has shown to be crucial for cardiac form and :unction. Alterations in fluid flow leads to various cardiac malformations including the cardiac valves. Specifically the Principal Investigator will focus on elucidating the effects that various flow parameters have on the morphology and gene regulation of key molecules in a unique 3-D model system established in the investigators laboratory. He will try to establish the mechanism that flow activates and where in the cascade of crucial signaling events fluid flow should be placed. The long term goal is to understand the importance of fluid flow n regulating the morphology of the developing cardiac valves. The knowledge gained from these experiments will create new strategies for the treatment of cardiac birth defects and valuable information concerning the design of tissue-engineered heart valves. A range of biochemical and cell biological studies on signaling mechanisms crucial to valve development are funded by NHLBI RO1 grant (HL072958-01). Stimulated by a new model system developed in the Pi's laboratory to study later stages of valve development which is amenable to directly studying the effect of fluid flow on valve formation, the Principal Investigator would like to expand the project to investigate this crucial question. The specific aims will test the hypothesis: that fluid flow in the heart regulates valvular morphogenetics and involves key signaling pathways. Our tenets will be tested in the following aims: 1) Determine the consequence of fluid flow on the differentiation and morphogenesis of valve leaflets; 2) Identification of altered expression of structural proteins in the Jak-3 deficient developing valves under flow; 3) Characterization of altered gene expression in endocardial cells exposed to fluid flow. As part of the KO2 project new. techniques will be introduced into the investigators already interdisciplinary laboratory. The Principal Investigator will undergo additional exposure to Rheology (study of fluid flow) and interactions with bioengineers and cardiovascular biologists will be expanded. The investigator has assembled a unique and dynamic group of investigators from which to draw upon. The Principal Investigator is well versed to answer truly fundamental questions regarding the role of fluid flow in regulating cardiac valve formation (End of Abstract)

描述（由申请人提供）： 这项 KO2 提案的目标是让首席研究员了解流体流动对调节控制发育中心脏瓣膜形态的关键基因的作用，为他在未来五年内提供超过 75% 的时间致力于研究。流体流动已被证明对于心脏的形态和功能至关重要。流体流动的改变会导致各种心脏畸形，包括心脏瓣膜。具体来说，首席研究员将重点阐明在研究人员实验室建立的独特 3D 模型系统中，各种流动参数对关键分子的形态和基因调控的影响。他将尝试建立流动激活的机制，以及流动在关键信号事件级联中应放置的位置。长期目标是了解流体流动对调节发育中的心脏瓣膜形态的重要性。从这些实验中获得的知识将为治疗心脏出生缺陷创造新的策略，并提供有关组织工程心脏瓣膜设计的宝贵信息。 NHLBI RO1 拨款 (HL072958-01) 资助了一系列关于对瓣膜发育至关重要的信号机制的生化和细胞生物学研究。在 Pi 实验室开发的一个新模型系统的刺激下，该模型系统可以研究阀门开发的后期阶段，该系统可以直接研究流体流动对阀门形成的影响，首席研究员希望扩大该项目以研究这一关键问题。具体目标将检验以下假设：心脏中的液体流动调节瓣膜形态发生并涉及关键信号通路。我们的原则将在以下目标中进行测试：1）确定流体流动对瓣叶分化和形态发生的影响； 2) 鉴定流动下 Jak-3 缺陷发育瓣膜中结构蛋白表达的改变； 3) 暴露于流体流动的心内膜细胞中基因表达改变的表征。作为 KO2 项目新的一部分。技术将被引入研究人员已经跨学科的实验室。首席研究员将进一步接触流变学（流体流动的研究），并扩大与生物工程师和心血管生物学家的互动。调查员组建了一个独特且充满活力的调查员团队可供借鉴。首席研究员擅长回答有关流体流动在调节心脏瓣膜形成中的作用的真正基本问题 （摘要完）