Bioreactor Organ Cultures of Serotonergic Valvulopathies

描述（由申请人提供）：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来研究体液（循环）剂在瓣膜细胞外基质（ECM）重塑中的作用。我们研究的长期目标是了解心脏瓣膜疾病的病因和进展，改进治疗方案，并减少瓣膜疾病的发病率。尽管去年美国有9.6万例心脏瓣膜疾病手术，但对其发病机制的实验研究却很少。尽管有证据表明存在这样的机制，特别是5 -羟色胺类药物芬氟拉明（减肥）和培高利特（帕金森综合征），但关于循环中药理学、毒性或自然发生的化学物质引起的重塑的研究也很少。我们的假设是体液制剂诱导瓣膜重塑，而在生物反应器中培养的瓣膜器官将提供关于重塑机制的新的时空信息。这些假设将通过实施以下具体目标来检验：(1)设计用于二尖瓣器官培养的简易机械调节生物反应器；(2)通过对器官培养瓣膜的材料特性、微观结构、ECM和细胞表型的评价，评估和优化生物反应器维持正常瓣膜在体特征的能力；(3)比较配置生物反应器模拟血清素能药物诱导的瓣膜病变后器官培养瓣膜组织的重塑情况。证明体液制剂可以诱导心脏瓣膜重构，进而提出调节机制，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心脏瓣膜进行无限的生物学和临床研究。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，但它们的瓣膜损伤活动尚不清楚。我们计划在培养箱中培养猪心脏瓣膜，并将其暴露于这些药物中，这将有助于我们了解药物的作用。在未来，类似的方法可以用来筛选潜在的破坏性药物和了解其他瓣膜疾病——这两者对公众健康都至关重要。

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.