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Integrated Control of Vascular Pattern Formation

血管模式形成的综合控制

基本信息

批准号：
6941662
负责人：
THOMAS C SKALAK
金额：
$ 72.4万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-01 至 2007-08-31
项目状态：
已结题

项目摘要

This Bioengineering Research Partnership assembles a team led by two biomedical engineers and a molecular physiologist to focus on the integrative control of vascular pattern formation. While vascular assembly and pattern formation will be needed as critical elements of successful therapeutic collateralization of progressively ischemic organs and in tissue engineering of various tissue substitutes in the future, remarkably little is known of the cells involved, the array of signal molecules and their genetic regulation, and the biophysical factors regulating the spatial and temporal dynamics of vascular pattern formation. Key questions now are: what is the origin of cells responsible for the investment of arterioles with contractile cells and what are the signals that control their proliferation, migration, and differentiation? An integrative systems approach is proposed to measure the dynamics of arteriolar pattern formation in vivo across time scales from the embryo to the adult, and spanning spatial scales from genes to cells to whole networks, and to create a new generation of computational approaches to understand the complex interplay of multiple interacting cells and signal molecules. The specific aims are 1) to determine the role of PDGF and TGF-beta in arteriolar pattern formation during embryonic development, 2) to determine the cell types involved, role of PDGF and TGF-beta signaling, and spatial and temporal patterns of arteriolar assembly in adults, and 3) to develop and use a new cell-based computer simulation to perform integrative spatio-temporal analysis of the arterialization process in the embryo and adult, including multi-signal control of fibroblast and smooth muscle cell proliferation, migration, and differentiation. The multidisciplinary team will utilize unique gene-targeted mice in conjunction with innovative in vivo measurements, and integration of the data into the new computational models will improve understanding of the gene circuitry regulating arteriolar pattern formation. This focused partnership with three investigators who have worked together previously brings a unique set of complementary tools to bear on the problem. Year 1 milestones are to obtain the first microvessel mappings of contractile cell recruitment in transgenic mouse embryonic tissues, to implement spatial guidance of arteriolar pattern formation through application of focal growth factors in adult window chambers, and to implement a novel computational model of arterialization that represents smooth muscle cells and fibroblasts discretely. The long term goal is to define the mechanisms that control arteriolar pattern formation, and to provide the basis for powerful therapeutic vascularization procedures that function in the native environment in vivo.

该生物工程研究合作伙伴组建了一个由两名生物医学工程师和一名分子生理学家领导的团队，专注于血管模式形成的综合控制。虽然血管组装和模式形成将成为未来成功治疗渐进性缺血器官和各种组织替代物的组织工程的关键要素，但对所涉及的细胞、信号分子阵列及其遗传调控以及调节血管模式形成的空间和时间动态的生物物理因素知之甚少。现在的关键问题是：负责将收缩细胞注入小动脉的细胞的起源是什么？控制其增殖、迁移和分化的信号是什么？提出了一种综合系统方法来测量体内小动脉模式形成的动态，从胚胎到成人的时间尺度，跨越从基因到细胞到整个网络的空间尺度，并创建新一代的计算方法来理解多个相互作用的细胞和信号分子的复杂相互作用。具体目标是 1) 确定 PDGF 和 TGF-β 在胚胎发育过程中小动脉模式形成中的作用，2) 确定所涉及的细胞类型、PDGF 和 TGF-β 信号传导的作用以及成人小动脉组装的空间和时间模式，以及 3) 开发和使用新的基于细胞的计算机模拟来对动脉化过程进行综合时空分析。胚胎和成人，包括成纤维细胞和平滑肌细胞增殖、迁移和分化的多信号控制。多学科团队将利用独特的基因靶向小鼠与创新的体内测量相结合，并将数据整合到新的计算模型中，将增进对调节小动脉模式形成的基因电路的理解。这种与三位先前合作过的研究人员的重点合作伙伴关系带来了一套独特的补充工具来解决这个问题。第一年的里程碑是获得转基因小鼠胚胎组织中收缩细胞募集的第一个微血管图谱，通过在成体窗室中应用局灶生长因子来实现小动脉模式形成的空间指导，并实现一种离散代表平滑肌细胞和成纤维细胞的新型动脉化计算模型。长期目标是确定控制小动脉模式形成的机制，并为在体内自然环境中起作用的强大的治疗性血管化程序提供基础。