Regulation of apoptotic priming and competence in healthy and cancerous cells

描述（由申请人提供）：以治愈为目的的化疗或放疗治疗人类癌症已导致数百万人的恶性肿瘤成功根除。 然而，在健康组织中诱导的凋亡性细胞死亡极大地限制了这些关键疗法的使用。这在儿科患者中尤其如此，例如，通常经历来自阿霉素治疗的心脏毒性或脑照射后的神经元凋亡。同样的治疗方法，成人的毒性明显低于儿童， 这种敏感性差异的基础是未知的。使用BH3分析，一种创新的工具， 通过测量细胞与凋亡阈值的接近程度，我们最近观察到在重要组织中如何调节凋亡的新的和惊人的差异，这些差异挑战了现有的 领域的教条。这些观察结果也为改善现有疗法和开发新型抗癌药物创造了机会。在这个提议中，我们计划首先全面了解细胞凋亡的差异调节如何影响细胞命运，以应对体内损伤或应激（目的1）。使用基因表达分析和小鼠模型，我们将确定控制这些途径的分子机制（目的2）。最后，我们将利用我们新发现的知识来识别和开发能够降低当前治疗毒性或代表新型抗癌疗法的药物（目标3）。通过了解和调节健康细胞和癌细胞的细胞凋亡程序，我们将改善患者的预后。

DESCRIPTION (provided by applicant): Treatment of human cancers with chemotherapy or radiation with curative intent has led to the successful eradication of malignancies in millions of patients, yet the apoptotic cell death induced in healthy tissues drastically limits the use of thee crucial therapies. This is especially true in pediatric patients that, for example, commonly experience cardiotoxicity from doxorubicin treatment or neuronal apoptosis after brain irradiation. Adults exhibit dramatically less toxicity than children from these same treatments but the basis for this difference in sensitivity is unknown. Using BH3 profiling, an innovative tool to measure how close cells are to the threshold of apoptosis, we recently observed novel and striking differences in the how apoptosis is regulated in vital tissues that challenge the existing dogma in the field. These observations also create opportunities to improve existing therapies and develop novel classes of anti-cancer drugs. Within this proposal, we plan to first develop a comprehensive understanding of how differential regulation of apoptosis affects cell fate in response to damage or stress in vivo (Aim 1). Using gene expression analysis and mouse models, we will then identify the molecular mechanisms that control these pathways (Aim 2). Finally, we will utilize our newfound knowledge to identify and develop agents that will reduce toxicity from current treatments or represent novel classes of anti-cancer therapies (Aim 3). By understanding and modulating apoptosis programs in healthy and cancerous cells we will improve patient outcomes.