Tissue and Cellular Pharmacodynamics of Vascular Growths

描述(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，但惊人的组织培养和动物模型效应在临床上变得微不足道。血管生长因子的有效利用具有挑战性，主要是因为其复杂的结构使其不稳定，而且它们影响的生物学参数无处不在且受到严格调控。一些人解释了在理化性质上达到临床效果的困难。事实上，在动物和临床试验中，几乎只有受控释放才能产生积极的效果。最初的想法是，控释避开了快速清除，维持了释放，延长了受体-配体的相互作用。然而，具有相同物理化学参数的GF在受控释放时表现不同，这些差异在疾病状态下会加剧。因此，仅靠药代动力学清除不能解释为什么给药方式对生长因子生物学如此关键。三个聚合的、相互关联的事件控制着一旦释放到目标组织中的GF的生物学，我们将逐步检查这些事件在正常和疾病组织状态下的情况。它们包括组织结合、运输、沉积和分布，代谢、清除和降解，以及细胞间的通讯和信号传递。在这项修订的拨款中，我们建立了一个迭代计划，利用我们实验室开发的独特工具，将细胞和分子生物学、生长因子生物化学、材料科学、聚合物化学、体外和体内控制释放技术与数学建模相结合，将所有这些元素整合在一起。我们将具体：1检查不同疾病状态和不同给药方式下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限制细胞与生长因子的相互作用；3表征细胞间隙连接信号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生物学的了解，并可能增加我们围绕这些化合物开发治疗方法的手段。

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.