Genetic Modifiers of Radiation Therapy-Induced Cardiotoxicity

放射治疗引起的心脏毒性的基因修饰

• 批准号: 9797491
• 负责人: Carmen Bergom
• 金额: $ 41.87万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9797491
• 关键词: Area; Breast Cancer Treatment; Cancer Patient; Candidate Disease Gene; Cardiac; Cardiac Myocytes; Cardiotoxicity; Cessation of life; Chromosome Mapping; Chromosomes, Human, Pair 3; Complex; DNA Repair; EFRAC; Echocardiography; Endothelial Cells; Exposure to; Gene Expression; Genes; Genetic; Genetic Models; Genetic study; Genome; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Heritability; Human; Hypertrophy; Individual; Inherited; Knowledge; Link; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mediator of activation protein; Mitochondria; Modeling; Mutation; Myocardial; Necrosis; Oxidative Stress; Pathway interactions; Patients; Pericardial effusion; Phenotype; Pleural effusion disorder; Pre-Clinical Model; Predisposition; Radiation; Radiation Dose Unit; Radiation Tolerance; Radiation Toxicity; Radiation therapy; Radiation-Induced Change; Rat Strains; Rattus; Resistance; Risk; Severities; Symptoms; Techniques; Testing; Therapeutic; Tissues; Toxic effect; base; congenic; consomic; differential expression; efficacy testing; genetic variant; heart damage; high risk; in vivo; mitochondrial dysfunction; new therapeutic target; novel; patient stratification; phenotypic data; prevent; radiation risk; rat genome; stem; targeted agent; transcriptome sequencing

Radiation therapy is an important treatment received by over 50% of cancer patients. Exposure to radiation during the treatment of breast and lung cancers frequently causes collateral damage to cardiac tissue (i.e., cardiotoxicity), which can limit the utility of radiation and overall long-term benefits of this therapeutic option. In patients who receive cardiac radiation, progressive heart disease, heart failure, and death can occur. Mounting evidence suggests that complex genetic modifiers contribute to the risk of radiation-induced toxicities in cancer patients, yet these genetic modifiers remain largely unknown and poorly understood. No genetic variants are currently used to guide radiation dose constraints to the heart, and no therapies currently exist to protect against radiation-induced cardiotoxicity. We have developed the first genetic model to identify heritable modifiers of radiation- induced cardiotoxicity, using a rat model with gene substitutions (consomic rats) to identify regions of the genome responsible for differences in cardiac radiation sensitivity between two rat strains. Our preliminary results indicate that it may be possible to identify individuals at higher risk for radiation- induced heart disease based upon the presence of an inheritable 25 Mb region of rat chromosome 3 (0.9% of the genome) that contains genetic variants that enhance radiation-induced cardiotoxicity. This model demonstrates that (A) mitochondrial-related gene pathways are highly differentially expressed in the sensitive versus resistant rats one week after localized cardiac radiation, (B) hypertrophy and decreased contractility is detected at 12 weeks after radiation in the more sensitive rats, and (C) by 20 weeks after radiation, large areas of myocardial necrosis are present in the more sensitive rats. Our model provides a framework to define important phenotypic changes that stem from genetic variants to enhance radiotoxicity from cardiac radiation. We hypothesize that genetic modifier(s) of radiation-induced cardiotoxicity reside within the 25 Mb candidate region that we have localized to rat chromosome 3. We further hypothesize that the genetic modifier(s) within the candidate region are mechanistically linked to cardiomyocyte mitochondrial dysfunction that leads to cardiotoxicity in the sensitive rats after radiation. To test these hypotheses, we will (1) Use genetic mapping to identify genetic variant(s) that enhance radiation-induced cardiotoxicity in the 25 Mb region of rat chromosome 3; (2) Identify the pathophysiological and genetic mechanism(s) underlying radiation-induced cardiotoxicity findings of altered mitochondrial gene expression, cardiac hypertrophy and decreased contractility, and increased cardiac necrosis associated with the 25 Mb region of rat chromosome 3; and (3) Test the efficacy of novel mitochondrial-targeted agents to prevent or mitigate radiation-induced cardiotoxicity.

放射治疗是超过50%的癌症患者接受的重要治疗。暴露于 在治疗乳腺癌和肺癌时，放射线经常会对人体造成附带损害， 心脏组织（即，心脏毒性），这可能会限制辐射的效用和整体长期效益 这种治疗方法的选择。在接受心脏放射治疗的患者中，进行性心脏病，心脏 失败和死亡都可能发生。越来越多的证据表明，复杂的遗传修饰剂有助于 癌症患者中辐射诱导毒性的风险，但这些遗传修饰剂仍然主要 不为人知，知之甚少。目前没有遗传变异用于指导辐射剂量 限制心脏，目前还没有治疗方法可以防止辐射引起的心脏病。 心脏毒性我们开发了第一个遗传模型来识别辐射的遗传修饰剂- 诱导的心脏毒性，使用具有基因取代的大鼠模型（consomic大鼠）来鉴定 基因组负责两种大鼠品系之间心脏辐射敏感性的差异。我们 初步结果表明，有可能确定辐射风险较高的个人， 基于大鼠3号染色体的可遗传的25 Mb区域的存在而诱发的心脏病 (0.9%的基因组），其含有增强辐射诱导的心脏毒性的遗传变异。 该模型表明，（A）尿道相关基因通路高度差异 局部心脏放射后一周，敏感大鼠与抗性大鼠中的表达，（B） 在放射后12周检测到肥大和收缩力降低， 大鼠，和（C）辐射后20周，大面积的心肌坏死存在于更多的 敏感的老鼠我们的模型提供了一个框架来定义重要的表型变化， 基因变异来增强心脏辐射的辐射毒性。我们假设基因 辐射诱导的心脏毒性的修饰物位于我们所获得的25 Mb候选区域内。 定位于大鼠3号染色体。我们进一步假设，基因组中的遗传修饰剂 候选区域在机制上与心肌细胞线粒体功能障碍有关， 辐射后敏感大鼠的心脏毒性。为了验证这些假设，我们将（1）使用遗传 在25 Mb中进行定位以识别增强辐射诱导的心脏毒性的遗传变异 大鼠3号染色体区域;（2）确定其病理生理和遗传机制 放射诱导的心脏毒性：线粒体基因表达改变，心脏 心肌肥厚和收缩力降低，以及与25 Mb相关的心肌坏死增加 大鼠3号染色体区域;和（3）测试新的尿道靶向剂的功效， 预防或减轻辐射引起的心脏毒性。