Regulation of apoptotic priming and competence in healthy and cancerous cells

描述(申请人提供)：用化疗或放射疗法治疗人类癌症，有治疗意图，已导致数百万人成功根除恶性肿瘤 然而，健康组织中诱导的凋亡细胞死亡极大地限制了这三种关键疗法的使用。这在儿科患者中尤其如此，例如，他们通常会经历阿霉素治疗的心脏毒性或脑照射后神经元的凋亡。成年人的毒性比儿童要小得多，但 这种敏感度差异的基础尚不清楚。使用BH3评测，这是一种创新的工具 测量细胞离凋亡阈值有多近，我们最近观察到在重要组织中如何调控细胞凋亡的新的和显著的差异，这些差异挑战了现有的 赛场上的教条。这些观察结果也为改进现有疗法和开发新型抗癌药物创造了机会。在这项提案中，我们计划首先全面了解细胞凋亡的不同调控如何影响细胞命运，以应对体内的损伤或应激(目标1)。利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(目标2)。最后，我们将利用我们新发现的知识来确定和开发将减少当前治疗方法的毒性或代表新的抗癌疗法类别的药物(目标3)。通过了解和调节健康和癌细胞的凋亡程序，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.