Regulation of apoptotic priming and competence in healthy and cancerous cells

健康细胞和癌细胞中凋亡启动和能力的调节

• 批准号: 8767377
• 负责人: Kristopher Andrew Sarosiek
• 金额: $ 9.05万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8767377
• 关键词: Adult; Affect; Antineoplastic Agents; Apoptosis; Apoptotic; Award; BAX gene; Biological Assay; Brain; Cancerous; Cardiotoxicity; Cell Death; Cells; Child; Childhood; Competence; Cranial Irradiation; Development; Doxorubicin; Employee Strikes; Exhibits; Gene Expression Profiling; Health; Heart; Human; Infant; Kidney; Knowledge; Malignant Neoplasms; Measurement; Measures; Mentors; Modeling; Molecular; Mus; Names; Outcome; Output; Pathway interactions; Patients; Phase; Physiological; Proteins; Radiation; Regulation; Role; Signal Pathway; Signal Transduction; Stress; Testing; Tissues; Toxic effect; Work; arm; base; cancer cell; cancer therapy; chemotherapy; design; experience; high throughput screening; human cancer mouse model; improved; in vivo; infancy; inhibitor/antagonist; innovation; irradiation; killings; mouse model; neuron apoptosis; novel; postnatal; pre-clinical; pro-apoptotic protein; programs; response; small molecule; therapy development; tool; transcription factor; transcription factor USF

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.

描述（由申请人提供）：通过具有治愈性目的的化疗或放疗来治疗人类癌症，已成功根除数百万人的恶性肿瘤。 然而，健康组织中诱导的细胞凋亡极大地限制了这些关键疗法的使用。对于儿科患者尤其如此，例如，他们通常会因阿霉素治疗而出现心脏毒性，或在脑部照射后出现神经元凋亡。接受相同治疗的成人表现出的毒性明显低于儿童，但 这种敏感性差异的基础尚不清楚。使用 BH3 分析这一创新工具 为了测量细胞与细胞凋亡阈值的接近程度，我们最近观察到细胞凋亡在重要组织中的调节方式存在新颖且显着的差异，这些差异挑战了现有的细胞凋亡阈值。 领域内的教条。这些观察结果还为改进现有疗法和开发新型抗癌药物创造了机会。在该提案中，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响应体内损伤或应激（目标 1）。然后，我们将利用基因表达分析和小鼠模型来确定控制这些途径的分子机制（目标 2）。最后，我们将利用新发现的知识来识别和开发能够减少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凋亡程序，我们将改善患者的治疗结果。