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: 10472464
• 负责人: J. MARK CLINE
• 金额: $ 374.85万
• 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: 2020-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10472464
• 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; 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; ultrasound

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.

抽象/总结