3D Angiogenesis Assay for Heart Study

描述（由申请人提供）：血管生成是指从现有血管系统中生长出新血管。它涉及许多疾病和学科，包括心脏病，其中它在心肌梗死后缺血组织的修复中起重要作用。心脏病是美国第二大死亡原因。一系列令人失望的临床试验使缺血性心脏病的有效血管生成疗法的希望破灭。尽管血管生成的重要性，但缺乏有效的血管生成测定，这阻碍了血管生成治疗剂的开发。虽然存在许多可以提供关于血管生成的特定、狭窄方面的信息的体外和体内筛选测定，但通常很难解释这些测定的结果如何与血管生成实际表现的生理相关3D微观组织水平有关。特别是，有一个显着缺乏的测定，提供直接的信息，毛细血管形态和功能在原位，即使这最终是最重要的方面血管生成。该建议是在原位组织水平上开发高通量3D血管生成测定。它通过采用高速3D显微成像，多光谱检测，先进的组织标记协议和高内容图像分析软件来实现这一目标。作为第一个应用程序，我们将应用这一研究心肌缺血的血管生成反应成纤维细胞生长因子（bFGF）。我们相信这种检测方法将成为基础研究人员的一种有价值的工具，并在后期药物开发过程中为制药公司提供关于是否继续开发候选药物的关键信息。公共卫生相关性：该提案描述了一种新的血管生成检测方法的开发，我们将其应用于心脏病的研究。其关键创新是微血管的高度详细的3D图像，以及将其返回到组织生理学，组成和生化状态的能力。它具有降低在动物模型中进行血管生成测定的成本的强大潜力，以及提供高生理相关性并促进血管生成疗法用于治疗心脏病。

DESCRIPTION (provided by applicant): Angiogenesis is the growth of new blood vessels from the existing vasculature. It is implicated in many diseases and disciplines, including heart disease where it plays an important role in repair of ischemic tissue following myocardial infarction. Heart disease is the second leading cause of death in the United States. Hope for effective angiogenesis therapies in ischemic heart disease has been dampened by a series of mostly disappointing clinical trials. Despite the importance of angiogenesis, there is a lack of effective angiogenesis assays and this is hampering progress in developing angiogenic therapeutics. While there exist a number of vitro and in vivo screening assays which can provide information about specific, narrow aspects of angiogenesis, it is often very difficult to interpret how the results of these assays pertain to the physiological relevant 3D microscopic tissue level where angiogenesis actually manifests. In particular, there is a conspicuous lack of assays that provide direct information about capillary morphology and function in situ even though this is ultimately the most important aspect of angiogenesis. This proposal is for the development of a high throughput 3D angiogenesis assay at the in situ tissue level. It accomplishes this by employing high speed 3D microscopic imaging, multispectral detection, advanced tissue labeling protocols, and software for high content image analysis. As a first application we will apply this to study the angiogenic response to fibroblast growth factor (bFGF) in myocardial ischemia. We believe this assay will become a valuable tool for basic researchers and provide crucial information in the late drug development process to pharmaceutical companies on whether to continue the development of a drug candidate. PUBLIC HEALTH RELEVANCE: This proposal describes the development of a new angiogenesis assay which we apply to the study of heart disease. Its key innovations are highly detailed 3D images of the microvascular, and the ability to this back to tissue physiology, composition and biochemical state. It has the strong potential to reduce the cost of doing angiogenesis assays in animal models as well as offer high physiological relevance and advance the use of angiogenesis therapies for the treatment of heart disease.