Bioreactor Organ Cultures of Serotonergic Valvulopathies

描述(申请人提供)：该项目的目标是开发、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。我们研究的广泛的长期目标是了解心脏瓣膜疾病的原因和进展，改进治疗方案，并减少瓣膜疾病的发生率。尽管心脏瓣膜疾病去年在美国需要进行9.6万例手术，但对其发病机制的实验研究一直很少。尽管有证据表明存在这样的机制，但关于血液循环中药物、有毒或自然发生的化学物质引起的重塑的研究也很少，特别是5-羟色胺能药物芬福拉明(减肥)和培高利特(帕金森综合征)。我们的假设是，体液因子诱导瓣膜重塑，在生物反应器中培养的瓣膜器官培养将提供关于重塑机制的新的空间和时间信息。这些假说将通过实现下列特定目标来验证：(1)设计一种用于器官培养二尖瓣的简单机械条件生物反应器，(2)基于对器官培养瓣膜的材料特性、微观结构、细胞外基质和细胞表型的评估，评估和优化该生物反应器保持正常瓣膜体内特征的能力，以及(3)比较配置该生物反应器以模拟5-羟色胺能药物诱导的瓣膜病变后，器官培养瓣膜组织的重构情况。证明体液制剂可以诱导心脏瓣膜重塑，然后建议调节机制将把瓣膜研究带入综合生理学领域，使治疗剂的开发和测试成为可能，并可能减少手术干预的需要。此外，器官培养生物反应器系统将允许未来对正常、疾病、手术修复、药物治疗和组织工程心脏瓣膜进行无限制的生物和临床重点研究。相关：某些流行的5-羟色胺类药物进入血液并导致心脏瓣膜疾病，但它们对瓣膜的破坏活性尚不清楚。我们计划在孵化器中培养猪的心脏瓣膜，并将它们暴露在这些药物中，这将有助于我们了解这些药物的作用。未来，类似的方法可以用于筛选具有潜在破坏性的药物，并了解其他瓣膜疾病--这两种疾病都对公众健康至关重要。

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.