Tissue and Cellular Pharmacodynamics of Vascular Growths

血管生长的组织和细胞药效学

基本信息

批准号：
6856515
负责人：
Elazer R Edelman
金额：
$ 40.75万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-03-15 至 2006-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6856515
关键词：
SDS polyacrylamide gel electrophoresis angiogenesis angiogenesis factor biological signal transduction chromatography clearance rate confocal scanning microscopy gap junctions growth factor intracellular transport mathematical model pharmacokinetics protein binding protein transport swine tissue /cell culture

项目摘要

DESCRIPTION (provided by applicant): Growth factors(GF) control a range of physiological processes in multiple cell types. They should be ideal therapeutic compounds, and yet striking tissue culture and animal model effects become marginal in the clinic. Effective use of vascular GF is challenging principally because their complex structures make them unstable, and the biological parameters they affect are ubiquitous and tightly regulated. Some have explained the difficulty with achieving clinical effect on physicochemical properties. Indeed, it is almost exclusively controlled release that produces positive effects in animal and clinical trials. Initial thoughts were that controlled release circumvented rapid clearance, sustaining release and prolonging receptor-ligand interaction. However, GF with identical physicochemical parameters behave differentially when controlled release, with these differences being accentuated in disease states. Thus, pharmacokinetic clearance alone cannot explain why mode of delivery is so critical to GF biology. Three convergent, interrelated events control the biology of a GF once released to a target tissue and we will progressively examine these events in the normal and diseased tissue states. They include, tissue binding, transport, deposition and distribution of the GF, metabolism, clearance and degradation of the GF, and intercellular communication and signaling. In this revised grant we establish an iterative program which integrates all of these elements by making use of unique tools developed in our laboratory combining aspects of cellular and molecular biology, growth factor biochemistry, materials science, polymer chemistry and controlled-release technology in vitro and in vivo with mathematical modeling. We will specifically: 1 examine the impact of growth factor binding to target tissue under different disease states and after different modes of delivery; 2 define how cellular pharmacokinetics constrains cell-growth factor interactions, 3 characterize the impact on growth factor action of intercellular gap junction signaling; and 4 codify the biological regulatory response to growth factors using mathematical models. The results of these studies will add to our understanding of GF biology and possibly the means by which we develop therapies around these compounds.

描述（由申请人提供）：生长因子（GF）控制多种细胞类型中的一系列生理过程。它们应该是理想的治疗化合物，但令人震惊的组织培养和动物模型的影响在诊所变得边缘。有效使用血管GF是具有挑战性的，主要是因为它们的复杂结构使其不稳定，并且它们影响的生物学参数无处不在且受到严格调节。有些人解释了难以实现对物理化学特性的临床影响的困难。实际上，它几乎完全受控释放，在动物和临床试验中产生积极影响。最初的思想是受控释放规避了快速清除率，维持释放和延长受体配体相互作用。但是，在控制释放时，具有相同物理化学参数的GF行为会有所不同，其中这些差异在疾病状态下被强调。因此，仅药代动力学清除无法解释为什么输送方式对GF生物学如此至关重要。三个收敛性相互关联的事件控制着释放到靶组织的GF的生物学，我们将在正常和患病的组织状态下逐步检查这些事件。它们包括组织结合，转运，沉积和GF的分布，代谢，GF的清除和降解以及细胞间通信和信号传导。在这项修订的赠款中，我们建立了一个迭代程序，该程序通过利用在我们的实验室中开发的独特工具来整合所有这些元素，从而结合了细胞和分子生物学的各个方面，生长因子生物化学，材料科学，聚合物化学以及在体外和体内与数学模型中的体外和体内释放技术。我们将具体：1研究生长因子在不同疾病状态下和不同传递方式下与靶组织结合的影响； 2定义细胞药代动力学如何限制细胞生长因子相互作用，3表征对细胞间间隙连接信号的生长因子作用的影响；和4使用数学模型将生物调节响应编纂为生长因子。这些研究的结果将增加我们对GF生物学的理解，以及我们围绕这些化合物开发疗法的手段。