Growth of Normal Tissues: Radiobiological Implications

正常组织毒性是癌症放射治疗的剂量限制。这项工作的长期目标是了解辐射引起的细胞扰动以及导致剂量限制组织失效的潜在动力学，其动力学在很大程度上是未知的。这项提案涉及的基本问题是：“为什么器官在最初的损伤造成和识别后的几个月里才衰竭？组织崩溃的动态平衡控制是如何进行的？调节最终结果的种群动态参数的特征是什么？”正常组织通常被归类为急性反应或迟发性反应，这取决于辐射后潜伏期，在潜伏期之后，它们在功能上表现出损伤。这项建议侧重于肺(通常被认为是反应迟缓的正常组织)。这些特定的目标将建立正常的肺内稳态机制，这些机制在X射线照射后恢复正常组织功能中的作用以及角质形成细胞生长因子(KGF)治疗对内稳态的调节作用。生长因子为减轻正常组织的放射毒性提供了一种新的方法。然而，它们的合理使用需要更好地了解组织的种群动态，以便确定辐射防护策略。我们将详细描述特定亚群细胞的增殖、分化和凋亡状态，并确定辐射和KGF扰乱肺泡上皮细胞种群动态的特定动力学机制。这些实验将确定KGF保护肺免受辐射损伤的细胞机制。在照射时和照射后定期测量这些参数，将确定我们在单独照射或KGF预处理后对剂量和时间反应进行量化的群体动力学机制。首先，我们将验证这样的假设，即KGF在分次照射制度下给予时将保护肺，这是临床标准。其次，我们假设KGF对于挽救辐射损伤是有用的。我们将通过肺照射后使用KGF进行治疗来测试这一点。第三，我们将检验我们的假设，即KGF不会刺激少量残留肿瘤或微转移的增殖。如果KGF要在少量肿瘤可能残留的情况下进行后处理时发挥作用，这一点很重要。这项工作使用了一个新的分析框架来关联正常组织的增殖量和凋亡量。

Normal tissue toxicity is a dose-limitation for cancer radiotherapy. The long-term goal of this work is to understand the cellular perturbations that result from irradiation and the underlying dynamics that lead to failure of dose-limiting tissues whose dynamics are largely unknown. Fundamental questions, which this proposal addresses, are: "Why does the organ not fail until many months after the initial damage has been both inflicted and recognized? How does homeostatic control of the tissue breakdown? What are the characteristics of the population dynamic parameters which modulate the final outcome?" Normal tissues have become conventionally categorized as either acute- or late- responding depending on the latent periods after which they functionally express their damage following irradiation. This proposal focuses on lung (typically considered a late-responding normal tissue). The specific aims will establish the normal homeostatic mechanisms of the lung, the effects of these mechanisms in the restoration of normal tissue function after X- irradiation and the modulation of homeostasis by treatment with keratinocyte growth factor (KGF). Growth factors offer a novel means of mitigating normal tissue radiotoxicity. Their rational use, however, requires a better understanding of the population dynamics of tissues in order to define strategies for radioprotection. We will detail the proliferative, differentiation, and apoptotic status of defined subpopulations of cells and determine the specific kinetic mechanisms by which irradiation and KGF perturb the population dynamics of the alveolar epithelium. The experiments will determine the cellular mechanisms by which KGF protects the lung from radiation damage. Measurement of these parameters at the time of irradiation and periodically thereafter, will determine the population dynamic mechanisms that contribute to the dose- and time-responses we have quantitated after either radiation alone or following KGF pretreatment. Firstly, we will test the hypothesis that KGF will protect the lung when given in a fractionated irradiation regime, as is the clinical norm. Secondly, we hypothesize that KGF will be useful for salvage of radiation damage. We will test this by treating with KGF post- irradiation of the lung. Thirdly, we will test our hypothesis that KGF will not stimulate proliferation of small amounts of residual tumor or micrometastases. This is important if KGF is to be useful when given post-treatment when small amounts of tumor might remain. This work uses a new analytical framework to relate proliferative and apoptotic quantities of normal tissues.