Bioreactor Organ Cultures of Serotonergic Valvulopathies

血清素能瓣膜病的生物反应器器官培养

基本信息

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
项目类别：
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

项目摘要

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）：该项目的目的是开发，验证和应用器官培养物生物反应器系统来研究瓣膜外基质（ECM）重塑中体液（循环）剂的作用。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，以改善治疗选择并减少瓣膜疾病的发生率。尽管去年在美国需要进行96,000次手术，但对其发病机理的实验研究很少。尽管有证据表明存在这种机制，但在循环中，药理学，有毒或天然存在的化学物质引起的重塑的研究也很少，尤其是使用5-羟色胺芬氏胺（体重减轻）和pergolide（帕金森综合征）。我们的假设是，体液剂会诱导瓣膜重塑，而生物反应器中生长的瓣膜器官培养物将提供有关重塑机制的新型空间和时间信息。这些假设将通过实施以下特定目的来测试：（1）设计一种简单的机械调节生物反应器，用于器官培养二尖瓣，（2）评估和优化生物反应器维持基于对材料，Microlstructire，Ecm和Cell Pastifers of Ornant of Ornant of Ornant of Ornant of Ornant of Ornant of Organife and Ornripter of Ornant of Ornant of Ornant of Ornant of Ornant of Ornant of Organife in Ornant of Ornant of Organife in Ornant of Organife and Ornanter的器官（3）的生物反应器在体内特征的能力（配置生物反应器后，培养的瓣膜组织模拟血清素能药物诱导的瓣膜病。证明体液剂可以在心脏瓣膜中诱导重塑，然后提出调节机制会将瓣膜研究引入整合生理学领域，使治疗剂的开发和测试可以减轻手术干预的需求。此外，器官培养物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心脏瓣膜的正常，患病，手术修复和临床上的未来无限。相关性：某些流行的5-羟色胺样药物进入血液并引起心脏瓣膜疾病，但其瓣膜破坏活动尚不清楚。我们在孵化器中种植猪心脏瓣膜并将其暴露于这些药物的计划将有助于我们了解药物的作用。将来，可以使用类似的方法来筛查潜在的破坏药物并了解其他瓣膜疾病 - 既对公共卫生必不可少。