Tissue and Cellular Pharmacodynamics of Vascular Growths

血管生长的组织和细胞药效学

• 批准号: 6581788
• 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
• 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/6581788
• 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

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，但在临床上，显着的组织培养和动物模型作用变得边缘。血管GF的有效使用是具有挑战性的，主要是因为它们的复杂结构使它们不稳定，并且它们影响的生物学参数是普遍存在的且受到严格调控。有些人解释了难以实现理化性质的临床效果。事实上，在动物和临床试验中产生积极效果的几乎完全是控制释放。最初的想法是控制释放规避快速清除，持续释放和延长受体-配体相互作用。然而，具有相同理化参数的GF在控释时表现出差异，这些差异在疾病状态下加剧。因此，单独的药代动力学清除率不能解释为什么递送模式对GF生物学如此重要。三个收敛的，相互关联的事件控制生物学的GF一旦释放到靶组织，我们将逐步检查这些事件在正常和病变组织状态。它们包括GF的组织结合、运输、沉积和分布、GF的代谢、清除和降解以及细胞间通讯和信号传导。 在这个修订后的补助金，我们建立了一个迭代程序，通过利用我们实验室开发的独特工具，结合细胞和分子生物学，生长因子生物化学，材料科学，聚合物化学和控制释放技术在体外和体内的数学建模方面，整合了所有这些元素。我们将具体：1检查在不同疾病状态下和不同递送模式后生长因子与靶组织结合的影响; 2定义细胞药代动力学如何约束细胞-生长因子相互作用; 3表征细胞间间隙连接信号传导对生长因子作用的影响; 4使用数学模型编码对生长因子的生物调节反应。这些研究的结果将增加我们对GF生物学的理解，并可能增加我们围绕这些化合物开发疗法的方法。