Angiogenesis Model for Aging Research

 描述(申请人提供)：旨在操纵微循环的疗法需要控制血管生成的能力，血管生成的定义是从现有血管长出新的毛细血管。在与年龄相关的病理(癌症、视网膜病变、类风湿性关节炎)中 血管生成将是有益的。在其他方面(心肌梗塞、中风、高血压)，促进血管生成将是可取的。大多数治疗方法都是使用成年动物模型开发的，但这种方法存在问题，没有考虑到血管生成受损和年龄导致的固有变化。因此，需要新的与老龄化相关的模型。这项建议的总体目标是为了解老年组织中受损的血管生成提供新的信息，同时建立一种创新的体外组织培养模型，使在完整的老年微血管网络中进行实时、机械的研究成为可能。目前还不存在这样的模式。我们的实验室最近证明，在培养的成年大鼠肠系膜组织中，网络可以用来探测周细胞-内皮细胞之间的相互作用。虽然周细胞在血管生成中起着关键作用，是干细胞治疗的重要靶点，但令人惊讶的是，人们对它们在衰老过程中的功能几乎一无所知。新的初步数据表明有两个发现：老化网络中的毛细血管增加了成熟周细胞的覆盖率，人类老化的骨髓来源干细胞比成人细胞增加了周细胞的命运。拟议的研究将利用大鼠肠系膜培养模型的能力来测试一个新的总体假设，即在衰老过程中成熟周细胞覆盖率增加是导致血管生成受损的原因。通过这样做，我们的结果将为机械性衰老研究和临床前应用治疗评估提供新的工具。目的1：验证NG2介导的周细胞-内皮细胞在血管生成过程中的相互作用在老年微血管网络中受损的假说。目的：验证衰老的人骨髓来源干细胞(BMSCs)在血管生成过程中周细胞命运增加的假设。目的：评价血管内皮细胞和周细胞靶向血管生成药物治疗对老年微血管网络的影响。这项拟议的工作将提供有关衰老过程中周细胞功能和干细胞命运变化的新信息。这些发现将为衰老研究引入新的方向。这一结果也将证明一种新的体外模型作为一种新工具的有效性。

 DESCRIPTION (provided by applicant): Therapies aimed at manipulating the microcirculation require the ability to control angiogenesis, defined as the sprouting of new capillaries from existing vessels. In age-related pathologies (cancer, retinopathies, rheumatoid arthritis) blocking angiogenesis would be beneficial. In others (myocardial infarction, stroke, hypertension), promoting angiogenesis would be desirable. Most therapies are developed using adult animal models, yet this approach is problematic and does not account for the impaired angiogenesis and inherent changes resulting from age. Thus, new aging relevant models are required. The overall goal of this proposal is to provide novel information towards understanding impaired angiogenesis in aged tissues, while establishing an innovative ex vivo tissue culture model that enables real-time, mechanistic investigation in an intact aged microvascular network. No such model currently exists. Our laboratory has recently demonstrated that in cultured adult rat mesentery tissues, networks can be used to probe pericyte-endothelial cell interactions during. While pericytes are known to play a critical role in angiogenesis and are important targets for stem cell based therapies, surprisingly almost nothing is known about their function during aging. New preliminary data suggests two discoveries: that capillaries in aged networks have increased coverage of mature pericytes and that human aged bone marrow derived stem cells have increased pericyte fate versus adult cells. The proposed studies will leverage the capabilities of the rat mesentery culture model to test a novel overall hypothesis that increased mature pericyte coverage during aging is responsible for impaired angiogenesis. In doing so, our results will provide a new tool for mechanistic aging research and applied pre-clinical therapy evaluation. Aim 1: To test the hypothesis that NG2 mediated pericyte-endothelial cell interactions during angiogenesis are impaired in aged microvascular networks. Aim 2: To test the hypothesis that aged human bone marrow derived stem cells (BMSCs) display an increased pericyte fate during angiogenesis. Aim 3: To evaluate the effect of endothelial and pericyte targeted angiogenic drug therapies on aged microvascular networks. The proposed work will provide new information regarding altered pericyte function and stem cell fate during aging. These discoveries will introduce a new direction for aging research. The results will also demonstrate the usefulness of a new ex vivo model as a new tool.