The morphogenetic regulation of cardiac valves by fluid flow.

描述（由申请人提供）： 该KO 2提案的目标是让主要研究者了解流体流动在调节控制心脏瓣膜发育形态的关键基因方面的作用，为他提供超过75%的时间用于未来五年的研究。液体流动已被证明对心脏的形态和功能至关重要。流体流动的改变导致包括心脏瓣膜在内的各种心脏畸形。具体而言，主要研究者将专注于阐明各种流动参数对研究者实验室建立的独特3-D模型系统中关键分子的形态和基因调控的影响。他将试图建立流动激活的机制，以及在关键信号事件的级联中，流体流动应该被放置在哪里。长期目标是了解流体流动在调节发育中的心脏瓣膜形态中的重要性。从这些实验中获得的知识将为心脏出生缺陷的治疗创造新的策略，并为组织工程心脏瓣膜的设计提供有价值的信息。一系列关于对瓣膜开发至关重要的信号传导机制的生化和细胞生物学研究由NHLBI RO 1资助（HL 072958 -01）。在Pi实验室开发的新模型系统的刺激下，主要研究员希望扩大该项目，以研究这一关键问题。具体的目标将测试假设：心脏中的流体流动调节瓣膜形态发生学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）表征暴露于流体流动的内皮细胞中基因表达的改变。作为KO 2新项目的一部分。技术将被引入研究人员已经跨学科的实验室。主要研究者将接受额外的流变学（流体流动研究），并将扩大与生物工程师和心血管生物学家的互动。调查员已组建了一个独特和充满活力的调查员小组，可从中汲取经验。主要研究者精通回答关于液体流动在调节心脏瓣膜形成中的作用的真正基本问题 (End摘要）

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)