The Wake Forest Nonhuman Primate Radiation Survivor Cohort

摘要/总结 辐射暴露的急性影响是紧急医疗响应和缓解工作的重点，但是 辐射损伤的主要负担在于延迟效应。这些暴露的晚期且通常是长期的影响 对正常健康组织的影响包括导致器官功能障碍的细胞、分子和代谢变化 失败；纤维化；和肿瘤。辐射幸存者群体 (RSC) 是一个独特且不可替代的群体 非人类灵长类动物 (NHP) 辐射幸存者种群，满足国家识别和 了解辐射暴露的后期影响；提供急性生物标志物的长期结果验证 测量；并提供有关组织损伤和恢复的关键数据。 RSC 的 Wake 调查员 Forest 评估了 140 多只恒河猴单剂量全身暴露 1-8.5 Gy 的不良影响 猴子在辐射后被观察长达 15 年，其中有 38 只对照。该群体包括青少年和成人 暴露，雄性和雌性，以及接受或未接受缓解治疗的动物子集，例如 如造血生长因子或抗生素。观察包括年度临床周期 检查、影像学（超声、CT 和 MRI）、临床病理学以及最终的尸检。 目前已发现的主要疾病包括：（1）代谢性疾病和II型糖尿病； (2)心肌 舒张功能障碍伴纤维化； (3) MRI 检测到脑部病变的神经系统疾病； (4)慢性肾病 纤维化疾病； (5)胃肠道疾病导致慢性腹泻； (6) 免疫损害 反应能力受损； (7)肿瘤，主要包括肉瘤、造血系统肿瘤、上皮肿瘤和 神经内分泌类型。还可以看到其他典型的辐射效应，例如白内障和性腺萎缩 更高的剂量。同一动物出现多种疾病的情况很常见，高剂量动物中多达 8 种，伴有糖尿病 是最常见的合并症。拟议的新资助期的总体目标是 确定并研究这个独特的、受控的、良好的环境中辐射后发病率和死亡率的相关模式 通过与 NIH 资助的和其他联邦资助的机构合作和共享数据来定义 NHP 人群 调查人员。共享将包括样本（血液、组织、体液、微生物组）和数据（临床、成像、 病理学、基因序列、基因表达、免疫表型和其他数据类型） 调查员群体目前由 18 个机构的 62 名调查员组成，包括向新的 调查小组。该计划的具体目标是 (1) 识别并分享辐照后的模式 发病率； (2) 识别不同辐射诱导动物的基因组和生物标志物特征 疾病； (3) 评估先前缓解剂治疗的后期效果； (4) 细化队列以平衡年龄、性别、 剂量和缓解剂类型，以便最大限度地扩大从队列中得出的数据的推断范围。

Abstract/Summary Acute effects of radiation exposures are the focus of emergency medical responses and mitigation efforts, but the major burden of radiation injury lies in delayed effects. These late and usually long-term effects of exposure on normal healthy tissues include cellular, molecular, and metabolic changes leading to organ dysfunction and failure; fibrosis; and neoplasia. The Radiation Survivor Cohort (RSC) is a unique and irreplaceable population of nonhuman primate (NHP) radiation survivors, which serves the nation’s need to identify and understand the late effects of radiation exposure; provides long-term outcome validation of acute biomarker measurements; and provides critical data regarding tissue damage and recovery. RSC investigators at Wake Forest have assessed adverse effects of single-dose whole-body exposures of 1-8.5 Gy in over 140 rhesus monkeys observed for up to 15 years after irradiation, with 38 controls. The cohort includes juvenile and adult exposures, males and females, and subsets of animals that did or did not receive mitigating treatments such as hematopoietic growth factors or antibiotics. Observations have included an annual cycle of clinical examinations, imaging (ultrasound, CT and MRI), clinical pathology, and ultimately necropsy examinations. Major diseases identified to date include (1) metabolic disease and type II diabetes mellitus; (2) myocardial diastolic dysfunction with fibrosis; (3) neurologic disorders with MRI-detected brain lesions; (4) chronic renal disease with fibrosis; (5) gastrointestinal disease resulting in chronic diarrhea; (6) immune compromise with impaired response repertoire; (7) neoplasms, primarily including sarcomas, hematopoietic, epithelial, and neuroendocrine types. Other stereotypical radiation effects are seen, such as cataracts and gonadal atrophy at higher doses. Multiple disorders in the same animal were common, up to 8 in high-dose animals, with diabetes being the most common co-morbid condition. The overarching goal for the proposed new funding period is to identify and study relevant patterns of post-irradiation morbidity and mortality in this unique, controlled, well- defined NHP population, by collaborating and sharing data with NIH-funded and other federally-funded investigators. Sharing will include samples (blood, tissue, body fluids, microbiome) and data (clinical, imaging, pathology, gene sequence, gene expression, immunophenotyping and other data types) with an active investigator community currently consisting of 62 investigators across 18 institutions, including outreach to new investigative teams. The specific aims of this program are to (1) identify and share patterns of post-irradiation morbidity; (2) identify genomic and biomarker characteristics of animals with differing radiation-induced disorders; (3) assess late effects of prior mitigator treatment; and (4) refine the cohort to balance age, sex, dose, and mitigator type, in order to maximize the scope of inference of data derived from the cohort.