Angiogenesis Model for Aging Research

衰老研究的血管生成模型

• 批准号: 9030382
• 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 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9030382
• 关键词: Accounting; 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; Image; Integrins; Intervention Studies; Investigation; KDR gene; Laboratories; Link; Malignant Neoplasms; Mediating; Mesentery; Microcirculation; Modeling; Molecular Probes; Myocardial Infarction; PDGFRB gene; Pathology; Pericytes; Pharmacotherapy; Platelet-Derived Growth Factor; Play; Rattus; Research; Research Personnel; Retinal Diseases; Rheumatoid Arthritis; Role; Signal Transduction; Stem cells; Stroke; Sweat; Sweating; Testing; Therapeutic Intervention; Therapy Evaluation; Time; Tissues; Vascular Endothelial Growth Factors; Vascular System; Work; age related; aged; angiogenesis; capillary; 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（由适用提供）：旨在操纵微循环的疗法需要控制血管生成的能力，该疗法被定义为现有血管的新毛细血管发芽。与年龄有关的病理学（癌症，视网膜病，类风湿关节炎）阻塞 血管生成将是有益的。在其他情况下（心肌违规，中风，高血压），促进血管生成是可取的。大多数疗法是使用成人动物模型开发的，但是这种方法是有问题的，并且无法解释血管生成受损，并继承了年龄引起的变化。这是需要新的相关模型。该提案的总体目标是提供新的信息，以了解老年组织中的血管生成受损，同时建立了创新的离体组织培养模型，该模型可以实现对完整的老年微血管网络的实时机械投资。目前没有这样的模型。我们的实验室最近证明，在培养的成年大鼠肠系膜组织中，网络可用于探测周中周围的细胞细胞相互作用。虽然已知周细胞在血管生成中起关键作用，并且是基于干细胞疗法的重要靶标，但令人惊讶的是，在衰老过程中其功能几乎一无所知。新的初步数据表明了两个发现：老年网络中的毛细血管具有成熟周周的覆盖范围，并且人老化的骨髓衍生的干细胞的周期性命运与成人细胞相比增加了。拟议的研究将利用大鼠肠系膜培养模型的能力来检验一个新的总体假设，即衰老期间成熟的周细胞覆盖率增加是导致血管生成受损的。这样一来，我们的结果将为机械衰老研究和应用前临床治疗评估提供新工具。目的1：检验以下假设：在老年微血管网络中，血管生成过程中NG2介导的周细胞内皮细胞相互作用受损。目的2：检验以下假设：衰老的人骨髓衍生的干细胞（BMSC）在血管生成过程中表现出增加的周细胞命运。目标3：评估内皮和周细胞靶向血管生成药物疗法对老年微血管网络的影响。拟议的工作将提供有关衰老过程中周围周围功能和干细胞命运改变的新信息。这些发现将为衰老研究带来新的方向。结果还将证明新的离体模型作为新工具的有用性。