UNIVERSITY OF MARYLAND
The gastrointestinal tract is unique because of its highly proliferative stem cell population and therefore, is second only to the hematopoeitic system in sensitivity to radiation-induced injury. One of the most deleterious effects of radiation injury is the increased epithelial permeability that may facilitate bacterial translocation and sepsis. The effect of irradiation on the systemic and local (gut) immune response, which play a key role in the regulation of mucosal barrier function, is a novel component of the proposed studies. There are growth factors that may protect the gut mucosa against high-dose radiation induced injury or enhance its restoration including keratinocyte growth factor (KGF). The therapeutic goal for post irradiation injury is to maintain viability and to induce proliferation and maturation of the stem and epithelial cells of the gut mucosa. The overall goal of this application is to determine the mechanisms of radiation-induced alterations in gut structure and function and evaluate the efficacy of KGF and medical management in mitigating these alterations in a non-human primate (NHP) model of total abdominal irradiation. The application has two specific aims: 1) Determine the kinetics of irradiation-induced changes in the NHP gastrointestinal tract. We will use a model of abdominal only irradiation with bone-marrow shielded to limit the myelosuppressive effects to assess specific effects on the gut. The integrated and highly vertical approach will evaluate the full spectrum of radiation-induced changes in morphology and function beginning from the time of exposure and extending through a recovery period. Included in these studies will be the immune-mediated mechanisms involved in the disruption and reconstitution of mucosal barrier function; 2) Establish the treatment efficacy of KGF on irradiation-induced changes in the NHP gastrointestinal tract. Preliminary data show that KGF protects against radiation-induced loss of barrier function by affecting on crypt survival. We will determine the efficacy of post irradiation KGF treatment in parallel studies to those in Specific Aim 1. We have assembled a group of experienced investigators with expertise in gastrointestinal physiology, radiation biology and immunology. The experiments are designed to provide supportive data for a potential product development plan. The strong scientific environment and unique institutional resources are conducive to establishing a solid research platform for continued studies resulting in an FDA-approved product.