Tissue and Cellular Pharmacodynamics of Vascular Growths

描述（由申请人提供）：生长因子（GF）控制多种细胞类型的一系列生理过程。它们应该是理想的治疗化合物，但在临床中，显著的组织培养和动物模型效果却显得微不足道。有效利用血管GF具有挑战性，主要是因为它们复杂的结构使它们不稳定，它们影响的生物参数无处不在且受到严格调控。一些人解释了在物理化学性质上达到临床效果的困难。事实上，在动物和临床试验中，几乎只有控释才能产生积极的效果。最初的想法是控制释放绕过了快速清除，持续释放和延长受体-配体相互作用。然而，具有相同物理化学参数的GF在控释时表现不同，这些差异在疾病状态下更加突出。因此，单靠药代动力学清除率并不能解释为什么给药方式对GF生物学如此重要。一旦GF释放到靶组织，三个相互关联的事件控制着GF的生物学特性，我们将逐步研究正常和病变组织状态下这些事件。它们包括组织结合、运输、沉积和分布、代谢、GF的清除和降解以及细胞间通讯和信号传导。在这项修订后的拨款中，我们建立了一个迭代计划，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、聚合物化学和体外和体内控释技术等方面的数学建模，将所有这些元素整合在一起。我们将具体：1 .研究生长因子在不同疾病状态和不同给药方式下结合靶组织的影响；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描述细胞间隙连接信号对生长因子作用的影响；4利用数学模型编纂对生长因子的生物调控反应。这些研究的结果将增加我们对GF生物学的理解，并可能为我们开发针对这些化合物的治疗方法提供手段。

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.