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% 接受电离辐射的癌症患者患有辐射诱发的正常组织严重影响生活质量并在 5-10% 的人中出现潜在危及生命后果的伤害案件。由于患者之间存在很大差异，因此向所有患者提供的辐射量是很大程度上取决于对放射敏感的个体的耐受性。与生物遗传显着相关确定人群中不同频率的等位基因辐射反应的患者间变异性祖先将构成我们研究的基础。更好地了解可能有助于遗传因素确定性辐射反应将减轻不必要的医疗并发症。先验识别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选来确定剂量，以创建新的患者队列。我们将使用体外方法应用基因组学、转录组学和功能建模来高级确定个体最有可能增强辐射敏感性的基因型。由 100 个正常组织衍生的内部小组来自前列腺癌和乳腺癌患者的上皮细胞培养物将在电离辐射下使用。为此目的，将重点关注具有不同遗传血统的个体。辐射响应将是根据遗传变异和基因表达，单独和成组量化为连续变量辐射暴露后结合统计模型寻找遗传位点和上位 SNP-SNP 互动。为了扩大我们研究的范围和临床相关性，我们将把我们的发现与之前从接受放射治疗的患者那里获取了种系 DNA 样本，可用的临床数据如下以及辐射毒性评分。具体目标是：1）量化患者间辐射的关联编码种系变异的多基因外显子组的耐药性和敏感性以及使用辐射的基因表达与衰老相关的分泌表型与促炎细胞因子相关 2）筛选具有已知毒性评分的放射治疗患者的DNA样本并进行初步功能测试可在体外调节生殖系辐射相关变异的辐射敏感性。结果该提案将提供一个新的平台来筛选动物模型和患者的预测变异。这将使我们离基因组引导放射治疗更近一步，并使研究成为新颖的涉及辐射敏感性的机制。