Bioreactor Organ Cultures of Serotonergic Valvulopathies

血清素能瓣膜病的生物反应器器官培养

• 批准号: 7033688
• 负责人: KATHRYN JANE GRANDE-ALLEN
• 金额: $ 20.38万
• 依托单位: RICE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-15 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7033688
• 关键词: animal tissue; anorexic agent; antiparkinson drugs; bioengineering /biomedical engineering; bioreactors; biotechnology; cell migration; cell proliferation; dopamine agonists; extracellular matrix; fenfluramine; heart pharmacology; heart valve disorder; mitral valve; organ culture; pergolide; serotonin; serotonin inhibitor; swine; tissue engineering

DESCRIPTION (provided by applicant): The goal of this project is to develop, validate, and apply an organ culture bioreactor system to study the role of humoral (circulating) agents in valvular extracellular matrix (ECM) remodeling. The broad long-term objectives of our research are to understand the causes and progression of heart valve disease, to improve therapeutic options, and to reduce the incidence of valve disease. Although heart valve disease necessitated 96,000 surgeries in the U.S. last year, experimental research on its pathogenesis has been scant. There are also few studies about remodeling elicited by pharmacological, toxic, or naturally occurring chemicals in the circulation, despite evidence that such mechanisms exist, particularly with the serotonergic drugs fenfleuramine (weight loss) and pergolide (Parkinson's syndrome). Our hypothesis is that humoral agents induce valvular remodeling, and that valvular organ cultures grown in a bioreactor will provide novel spatial and temporal information about remodeling mechanisms. These hypotheses will be tested by implementing the following specific aims: (1) Design a simple mechanical conditioning bioreactor for organ culturing mitral valves, (2) Assess and optimize the bioreactor's ability to maintain the in vivo characteristics of normal valves based on an evaluation of the material properties, microstructure, ECM, and cell phenotypes in the organ cultured valves, and (3) Compare the remodeling of the organ cultured valve tissues after configuring the bioreactor to simulate serotonergic drug-induced valvulopathies. Demonstrating that humoral agents can induce remodeling in heart valves and then suggesting regulatory mechanisms would usher valve study into the field of integrative physiology, enable the development and testing of therapeutic agents, and could alleviate the need for surgical intervention. Additionally, the organ culture bioreactor system would permit unlimited future biologically and clinically focused studies of normal, diseased, surgically repaired, medically treated, and tissue engineered heart valves. Relevance: Certain popular serotonin-like medications enter the blood and cause heart valve disease, but their valve damaging activities are unclear. Our plan to grow pig heart valves in an incubator and expose them to these drugs will help us understand the drugs' actions. In the future, similar methods can be used to screen potentially damaging drugs and to understand other valve diseases - both essential to public health.

描述（由申请人提供）：本项目的目标是开发、验证和应用器官培养生物反应器系统，以研究体液（循环）因子在瓣膜细胞外基质（ECM）重塑中的作用。我们研究的广泛长期目标是了解心脏瓣膜疾病的原因和进展，改善治疗方案，降低瓣膜疾病的发病率。尽管去年美国有96，000例心脏瓣膜疾病需要手术，但对其发病机制的实验研究很少。也有一些关于重塑引起的药理学，毒性，或自然发生的化学物质在循环中，尽管有证据表明，这种机制存在，特别是与肾上腺素能药物芬夫拉明（减肥）和培高利特（帕金森氏综合征）。我们的假设是，体液剂诱导瓣膜重塑，并在生物反应器中生长的瓣膜器官培养物将提供新的空间和时间信息的重塑机制。将通过实现以下具体目标来检验这些假设：（1）设计用于器官培养二尖瓣的简单机械调节生物反应器，（2）基于对器官培养瓣膜中的材料性质、微观结构、ECM和细胞表型的评估，评估和优化生物反应器维持正常瓣膜的体内特性的能力，和（3）比较在配置生物反应器以模拟肾上腺素能药物诱导的瓣膜病之后器官培养的瓣膜组织的重构。证明体液因子可以诱导心脏瓣膜重塑，然后提出调节机制，将瓣膜研究引入综合生理学领域，使治疗药物的开发和测试成为可能，并可以减轻手术干预的需要。此外，器官培养生物反应器系统将允许对正常、患病、手术修复、医学治疗和组织工程化心脏瓣膜进行无限的未来生物学和临床集中研究。相关性：某些流行的类胡萝卜素药物进入血液并引起心脏瓣膜疾病，但其瓣膜损伤活动尚不清楚。我们计划在培养箱中培养猪的心脏瓣膜，并将它们暴露于这些药物中，这将有助于我们了解药物的作用。未来，类似的方法可用于筛选潜在破坏性药物并了解其他瓣膜疾病--这两者对公共卫生至关重要。