Angiogenesis Model for Aging Research

衰老研究的血管生成模型

• 批准号: 9337335
• 负责人: WALTER L MURFEE
• 金额: $ 27.77万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2017-09-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9337335
• 关键词: Adult; Aftercare; Age; Age-Months; Aging; Animal Model; Biological; Blood capillaries; Bone Marrow; CSPG4 gene; Cell Communication; Cell Lineage; Cell Proliferation; Cell Therapy; Cells; Data; Development; Drug Evaluation; Endothelial Cells; Environment; Evaluation; Goals; Human; Hypertension; Impairment; Integrins; Intervention Studies; Investigation; KDR gene; Laboratories; Link; Malignant Neoplasms; Mediating; Mesentery; Microcirculation; Modeling; Molecular Probes; Myocardial Infarction; Pathology; Pericytes; Pharmacotherapy; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor alpha Receptor; Play; Rat-1; Rattus; Research; Research Personnel; Retinal Diseases; Rheumatoid Arthritis; Role; Signal Transduction; Stem cells; Stroke; Sweat; Testing; Therapeutic Intervention; Therapy Evaluation; Time; Tissues; Vascular Endothelial Growth Factors; Vascular System; Work; age related; aged; angiogenesis; bone aging; capillary; cellular imaging; drug testing; inhibitor/antagonist; innovation; mature animal; novel; pre-clinical therapy; public health relevance; response; stem cell fate; therapy development; tissue culture; tool

 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.

 描述（由申请人提供）：旨在操纵微循环的治疗需要控制血管生成的能力，血管生成定义为从现有血管中萌发新的毛细血管。在与年龄相关的疾病（癌症、视网膜病变、类风湿性关节炎）中， 血管生成将是有益的。在其他情况下（心肌梗塞、中风、高血压），促进血管生成是可取的。大多数疗法是使用成年动物模型开发的，但这种方法是有问题的，并且没有考虑到受损的血管生成和由年龄引起的固有变化。因此，需要新的老化相关模型。该提案的总体目标是提供新的信息，以了解受损的血管生成在老年组织，同时建立一个创新的离体组织培养模型，使实时，在一个完整的老年微血管网络的机制调查。目前没有这样的模式。我们的实验室最近证明，在培养的成年大鼠肠系膜组织，网络可以用来探测周细胞内皮细胞的相互作用。虽然已知周细胞在血管生成中起关键作用，并且是基于干细胞的疗法的重要靶点，但令人惊讶的是，对它们在衰老过程中的功能几乎一无所知。新的初步数据表明了两个发现：老年网络中的毛细血管增加了成熟周细胞的覆盖率，以及人类老年骨髓源性干细胞与成人细胞相比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，即衰老过程中成熟周细胞覆盖率的增加是血管生成受损的原因。在这样做的过程中，我们的研究结果将提供一个新的工具，机械老化的研究和应用的临床前治疗评估。目标1：验证NG 2介导的周细胞-内皮细胞相互作用在血管生成过程中在老年微血管网络中受损的假设。 目的2：验证老年人骨髓源性干细胞（BMSCs）在血管生成过程中表现出周细胞命运增加的假设。目的3：评价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。这项工作将为衰老过程中周细胞功能和干细胞命运的改变提供新的信息。这些发现将为衰老研究引入一个新的方向。结果还将证明新的离体模型作为新工具的有用性。