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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：
6655666
负责人：
THOMAS C SKALAK
金额：
$ 71.56万
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 2006-08-31
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.

该生物工程研究伙伴关系由两名生物医学工程师和一名分子生理学家领导的团队组成，专注于血管模式形成的综合控制。虽然血管组装和模式的形成将需要作为成功的治疗性抵押渐进缺血器官和在组织工程的各种组织替代品在未来的关键要素，显着鲜为人知的是，涉及的细胞，信号分子的阵列和它们的遗传调控，以及生物物理因素调节的空间和时间动态的血管模式的形成。现在的关键问题是：负责小动脉内收缩细胞的细胞来源是什么？控制它们增殖、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从胚胎到成人的时间尺度上的体内小动脉模式形成的动态，并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。具体目的是1）确定PDGF和TGF-β在胚胎发育期间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中小动脉组装的空间和时间模式，3）开发和使用新的基于细胞的计算机模拟来执行集成空间-胚胎和成人动脉化过程的时间分析，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结合创新的体内测量，并将数据整合到新的计算模型中，将提高对调节小动脉模式形成的基因电路的理解。与三名以前曾一起工作的调查人员的这种有重点的伙伴关系带来了一套独特的互补工具来解决这个问题。第一年的里程碑是获得第一个微血管映射的收缩细胞招聘在转基因小鼠胚胎组织中，通过应用局部生长因子在成人窗口室实现小动脉模式形成的空间指导，并实现一种新的计算模型的动脉化，代表平滑肌细胞和成纤维细胞离散。长期目标是确定控制小动脉模式形成的机制，并为在体内天然环境中发挥作用的强大治疗性血管形成程序提供基础。