Germline Genetic Modifiers of Radiation Response

辐射反应的种系遗传修饰剂

基本信息

批准号：
10741022
负责人：
John Tyson McDonald
金额：
$ 40.11万
依托单位：
SRI INTERNATIONAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-19 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10741022
关键词：
Acute Address Affect African American Aftercare Age Algorithms Alleles American Animal Model Biological Biological Assay Breast Breast Cancer Patient Cancer Patient Cancer Survivor Caucasians Cell Culture Techniques Cell Cycle Cell Line Cells Clinical Clinical Data Clustered Regularly Interspaced Short Palindromic Repeats Code Correlation Studies DNA DNA sequencing Data Dermal Diagnosis Epithelial Cells European Exons Exposure to Frequencies Gene Expression Gene Frequency Genes Genetic Genomics Genotype Germ-Line Mutation Goals Health In Vitro Incidence Individual Individual Differences Inflammatory Investigation Ionizing radiation Libraries Life Link Malignant Neoplasms Malignant neoplasm of prostate Mammary Gland Parenchyma Measures Modeling Mutagens Mutation NF1 gene Normal Cell Normal tissue morphology Outcome PALB2 gene Pathway interactions Patients Phenotype Population Precision therapeutics Proliferating Prostate Quality of life Radiation Radiation Dose Unit Radiation Oncology Radiation Tolerance Radiation Toxicity Radiation exposure Radiation induced damage Radiation therapy Radiation-Induced Gene Expression Radiobiology Reporting Research Project Grants Risk Sampling Single Nucleotide Polymorphism Statistical Models Surveys Testing Toxic effect United States United States National Institutes of Health Variant Woman caucasian American clinically relevant cohort combinatorial cytokine design exome expectation fitness genetic variant genomic locus improved in vitro testing inter-individual variation interpatient variability ionization irradiation knockout gene malignant breast neoplasm medical complication men mortality neoplasm registry next generation sequencing novel poor health outcome protein function radiation resistance radiation response radioresistant response risk variant screening senescence side effect survivorship tissue injury transcriptome transcriptome sequencing transcriptomics treatment response triple-negative invasive breast carcinoma tumor whole genome

项目摘要

Approximately 50% of cancer patients receiving ionizing radiation suffer from radiation-induced normal tissue injury that significantly affects quality of life and presents potentially life-threatening consequences in 5-10% of the cases. Due to a large range of interpatient variability, the amount of radiation delivered to all patients is largely guided by the tolerance of more radiosensitive individuals. Significant associations with biological genetic determinates of interpatient variability to radiation responses from alleles with differing frequencies by population ancestry will form the basis of our study. A better understanding of genetic factors that might contribute to a deterministic radiation response would mitigate unwanted medical complications. The a priori identification of genetic variants associated with increased radiation damage would be immensely useful for optimizing radiation dose through predictive screening to allow creation of novel patient cohorts. We will use an in vitro approach and apply genomics, transcriptomics, and functional modeling towards advanced determination of individual genotypes most at risk for enhanced radiation sensitivity. An in-house panel of 100 normal-tissue derived epithelial cell cultures from prostate and breast cancer patients will be used with exposure to ionizing irradiation. A focus on individuals with differing genetic ancestry will be used for this purpose. Radiation response will be quantified individually and in groups as continuous variables dependent on genetic variants and gene expression following radiation exposure in association with statistical modeling to find genetic loci and epistatic SNP-SNP interactions. In order to enlarge the scope and clinical relevance of our study, we will correlate our findings to previously acquired germline DNA samples from patients treated with radiation with available clinical data as well as radiation toxicity scores. The specific aims are: 1) to quantify the association of interpatient radiation resistance and sensitivity with polygenic exome coding germline variants and gene expression using a radiation associated senescence-associated secretory phenotype that is associated with pro-inflammatory cytokines and 2) screen DNA samples from radiation therapy patients with known toxicity scores and perform preliminary functional testing to modulate radiation sensitivity in vitro for germline radiation associated variants. The results of this proposal will provide a novel platform to screen for predictive variants in animal models and patients. This will bring us one step closer to genomically guided radiation treatment and enable the investigation novel mechanisms involved in radiation sensitivity.

大约50％的接受电离辐射的癌症患者患有辐射引起的正常组织严重影响生活质量并在5-10％中造成潜在威胁生命的后果的伤害案件。由于室内可变性范围很大，所有患者的辐射量是在很大程度上是受放射敏感个体的耐受性的指导。与生物遗传的重要关联确定人口频率不同的等位基因的辐射反应的室内变异性。祖先将构成我们研究的基础。更好地理解可能有助的遗传因素确定性的辐射反应会减轻不必要的医疗并发症。先验身份与辐射损伤增加相关的遗传变异对于优化辐射非常有用通过预测性筛查剂量，以允许创建新的患者同伙。我们将使用一种体外方法，并且将基因组学，转录组学和功能建模应用于个体的高级确定基因型最有可能提高辐射灵敏度的风险。派生的100个普通组织内部面板前列腺和乳腺癌患者的上皮细胞培养物将用于暴露于电离照射。对具有不同遗传血统的个体的重点将用于此目的。辐射反应将是单独量化，分组为连续变量，取决于遗传变异和基因表达辐射暴露与统计建模相关，以找到遗传基因座和上皮SNP-SNP 互动。为了扩大我们研究的范围和临床相关性，我们将使我们的发现与先前从接受辐射治疗的患者获得的生殖线DNA样品，并带有可用的临床数据以及辐射毒性得分。具体目的是：1）量化室内辐射的关联使用辐射的多基因外部编码种系变种和基因表达的抗性和灵敏度与促炎性细胞因子和相关的衰老相关分泌表型和 2）来自具有已知毒性评分并进行初步的放射治疗患者的筛查DNA样品功能测试以调节在体外对种系辐射相关变体的辐射敏感性。结果该提案将为动物模型和患者的预测变异提供一个新颖的平台。这将使我们更接近基因组引导的辐射处理，并使研究小说能够涉及辐射灵敏度的机制。