The Wake Forest Nonhuman Primate Radiation Survivor Cohort

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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.