The Wake Forest Nonhuman Primate Radiation Survivor Cohort

维克森林非人类灵长类辐射幸存者队列

• 批准号: 10462021
• 负责人: J. MARK CLINE
• 金额: $ 20万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-21 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10462021
• 关键词: Acute; Adolescent; Adult; Adverse effects; Age; Animals; Antibiotics; Atrophic; Autopsy; Biological Markers; Blood; Body Fluids; Bone Marrow; Brain; Cardiac; Cataract; Characteristics; Chronic Kidney Failure; Chronic diarrhea; Clinical; Clinical Pathology; Communities; Data; Data Set; Diabetes Mellitus; Disease; Distant; Dose; Epithelial; Equilibrium; Failure; Female; Fibrosis; Functional disorder; Funding; Gastrointestinal Diseases; Gene Expression; Genes; Genetic; Genetic Markers; Goals; Growth; Hematopoietic; Hematopoietic Cell Growth Factors; Hematopoietic Neoplasms; Human; Image; Immune; Immunophenotyping; Impaired cognition; Impairment; Incidence; Inflammatory; Institution; Interleukin-6; Knowledge; Late Effects; Lesion; Long-Term Effects; Macaca mulatta; Magnetic Resonance Imaging; Measurement; Measures; Medical emergency; Mesenchymal Cell Neoplasm; Metabolic; Metabolic Diseases; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Myocardial; Neoplasms; Neurosecretory Systems; Non-Insulin-Dependent Diabetes Mellitus; Organ; Outcome; Pathology; Pathway interactions; Pattern; Phenotype; Phylogenetic Analysis; Population; Radiation; Radiation Injuries; Radiation exposure; Recovery; Research Personnel; Resistance; Resources; Rodent; Sampling; Source; Supportive care; Survivors; Time; Tissues; Transforming Growth Factor beta; Ultrasonography; United States National Institutes of Health; Validation; Work; cancer therapy; clinical examination; cohort; comorbidity; data sharing; design; exome sequencing; forest; genomic biomarker; improved; inflammatory marker; interest; irradiation; macrophage; male; microbiome; mortality; nervous system disorder; nonhuman primate; outreach; programs; protective effect; radiation adverse effect; radiation effect; radiation mitigator; radiation resistance; response; sarcoma; sex; trait

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.

摘要/概要 辐射照射的急性影响是紧急医疗反应和缓解努力的重点， 辐射损伤的主要负担在于延迟效应。这些接触的晚期和通常是长期的影响 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， 衰竭、纤维化和瘤形成。辐射幸存者队列（RSC）是一个独特的和不可替代的 非人类灵长类动物（NHP）辐射幸存者的人口，这是国家需要识别和 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。维克的RSC调查人员 Forest评估了140多只恒河猴单次全身照射1-8.5戈伊的不良影响 对38只猴子进行了长达15年的辐照后观察，对照组为38只。该队列包括青少年和成年人 暴露，雄性和雌性，以及接受或未接受缓解治疗的动物亚组， 作为造血生长因子或抗生素。观察结果包括每年的临床周期 检查、成像（超声、CT和MRI）、临床病理学和最终尸检。 迄今发现的主要疾病包括：（1）代谢性疾病和II型糖尿病;（2）心肌梗死; 舒张功能障碍伴纤维化;（3）神经系统疾病伴MRI检测到的脑病变;（4）慢性肾功能不全 纤维化疾病;（5）导致慢性腹泻的胃肠道疾病;（6） 受损的反应库;（7）肿瘤，主要包括肉瘤、造血系统、上皮和 神经内分泌类型。其他典型的辐射效应，如白内障和性腺萎缩， 更高剂量同一只动物中的多种疾病很常见，高剂量动物中高达8种，伴有糖尿病 是最常见的合并症拟议新供资期的总体目标是 在这个独特的，控制良好的， 通过与NIH资助的和其他联邦资助的机构合作和共享数据， investigators.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）， 调查员社区目前由18个机构的62名调查员组成，包括与新的 调查小组。该计划的具体目标是（1）识别和共享辐照后的模式 （2）确定具有不同辐射诱导的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晚期效应;和（4）细化队列以平衡年龄，性别， 剂量和缓解剂类型，以最大限度地扩大从队列中得出的数据的推断范围。