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: 8918557
• 负责人: Kristopher Andrew Sarosiek
• 金额: $ 8.77万
• 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/8918557
• 关键词: Adult; Affect; Antineoplastic Agents; Apoptosis; Apoptotic; Award; BAX gene; Biological Assay; Brain; Cancerous; Cardiotoxicity; Cell Death; Cells; Child; 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; Radiation therapy; 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; pediatric patients; 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）：对化疗或具有治疗意图放射的人类癌的治疗导致成功地消除了数百万的恶性肿瘤 患者，然而，在健康组织中诱导的凋亡细胞死亡极大地限制了您关键疗法的使用。在小儿患者中尤其如此，例如，大脑照射后通常会因阿霉素治疗或神经元凋亡而经历心脏毒性。与这些治疗相同的儿童相比 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 测量细胞与凋亡阈值的距离，我们最近观察到在挑战现有的重要组织中凋亡的调节方式的新颖和引人注目的差异 田野里的教条。这些观察结果还创造了改善现有疗法并开发新型抗癌药物的机会。在该提案中，我们计划首先对凋亡的差异调节如何影响细胞命运，以应对体内的损伤或压力（AIM 1），对细胞命运有何影响。然后，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（AIM 2）。最后，我们将利用新发现的知识来识别和开发可以从当前治疗中降低毒性或代表新型抗癌疗法的药物（AIM 3）。通过了解和调节健康和癌细胞中的凋亡程序，我们将改善患者的结果。

项目成果

T Cells and Regulated Cell Death: Kill or Be Killed.

• DOI: 10.1016/bs.ircmb.2018.07.004
• 发表时间: 2019
• 期刊: International review of cell and molecular biology
• 作者: J. Spetz;Adam G. Presser;K. Sarosiek

Radiation-Induced Cardiovascular Toxicity: Mechanisms, Prevention, and Treatment.

• DOI: 10.1007/s11936-018-0627-x
• 发表时间: 2018-03-20
• 期刊: Current treatment options in cardiovascular medicine
• 作者: Spetz J;Moslehi J;Sarosiek K
• 通讯作者: Sarosiek K

Metabolic perturbations sensitize triple-negative breast cancers to apoptosis induced by BH3 mimetics.

• DOI: 10.1126/scisignal.abc7405
• 发表时间: 2021-06-08
• 期刊: Science signaling
• 影响因子: 7.3
• 作者: Daniels VW;Zoeller JJ;van Gastel N;McQueeney KE;Parvin S;Potter DS;Fell GG;Ferreira VG;Yilma B;Gupta R;Spetz J;Bhola PD;Endress JE;Harris IS;Carrilho E;Sarosiek KA;Scadden DT;Brugge JS;Letai A
• 通讯作者: Letai A