Integrated Control of Vascular Pattern Formation

血管模式形成的综合控制

基本信息

批准号：
6795832
负责人：
THOMAS C SKALAK
金额：
$ 72.5万
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.

这项生物工程研究伙伴关系组成了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。虽然将需要血管组装和模式形成，因为将来，逐渐缺血器官以及各种组织替代品的组织工程的成功治疗抵押品的关键要素，但对所涉及的细胞，信号分子的阵列及其遗传学因素及其生物物理因素的量化和时间造型的形式形式而言，鲜为人知。现在的关键问题是：负责用收缩细胞投资的细胞的起源是什么？控制它们的增殖，迁移和分化的信号是什么？提出了一种综合系统方法，以测量从胚胎到成人的时间尺度的体内动力学形成的动力学，并跨越从基因到细胞再到整个网络的空间尺度，并创建新一代的计算方法，以了解多个相互作用细胞和信号分子的复杂相互作用。具体目的是1）确定胚胎发育过程中PDGF和TGF-BETA在动脉模式形成中的作用，2）确定所涉及的细胞类型，PDGF和TGF-BETA信号传导的作用，以及在成人中开发和使用3）进行整合的ARTORALIOL SPATIOS SPAT的动脉组装过程的空间和时间模式，以进行整合的分析。胚胎和成人，包括对成纤维细胞和平滑肌细胞增殖，迁移和分化的多信号控制。多学科团队将通过创新的体内测量来利用独特的基因靶向小鼠，将数据集成到新的计算模型中将提高对调节小动脉模式形成基因电路的理解。与三名研究人员一起工作的这一集中伙伴关系以前为此带来了一套独特的补充工具来解决这个问题。第1年的里程碑是要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映射，以通过在成人窗室中应用焦点生长因子的应用来实施小动脉模式形成的空间指导，并实施一种新型的动脉化计算模型，该模型代表平滑肌细胞和纤维细胞的空间化。长期目标是定义控制动脉模式形成的机制，并为在体内在天然环境中起作用的强大治疗性血管化程序提供基础。