Novel Therapy for Post-Irradiation Insult to Gut Mucosa in Non-Human Primates

描述(申请人提供)：胃肠道是独一无二的，因为其高度增殖的干细胞群体，因此，在对辐射损伤的敏感性方面仅次于造血系统。辐射损伤最有害的影响之一是上皮通透性增加，这可能会促进细菌移位和败血症。辐射对全身和局部(肠道)免疫反应的影响在粘膜屏障功能的调节中起着关键作用，这是拟议研究的一个新组成部分。有一些生长因子可以保护肠粘膜免受高剂量辐射损伤或促进其修复，其中包括角质形成细胞生长因子(KGF)。照射后损伤的治疗目标是维持肠粘膜干细胞和上皮细胞的活性，并诱导其增殖和成熟。这项应用的总体目标是确定辐射诱导的肠道结构和功能变化的机制，并评估KGF和医疗管理在减轻非人类灵长类(NHP)全腹部照射模型中这些变化的有效性。该应用有两个特定的目的：1)确定NHP胃肠道辐射引起的变化的动力学。我们将使用仅腹部照射的模型，在骨髓屏蔽的情况下限制骨髓抑制效应，以评估对肠道的特定影响。综合和高度垂直的方法将评估从暴露时间到恢复期的辐射引起的形态和功能变化的全谱。这些研究将包括涉及黏膜屏障功能破坏和重建的免疫介导性机制；2)确定KGF对辐射诱导的NHP胃肠道变化的治疗效果。初步数据显示，KGF通过影响隐窝存活来保护机体免受辐射所致的屏障功能丧失。我们将通过平行研究来确定照射后KGF治疗的疗效。1.我们组建了一批经验丰富的研究人员，他们具有胃肠道生理学、放射生物学和免疫学方面的专业知识。这些实验旨在为潜在的产品开发计划提供支持数据。强大的科研环境和独特的机构资源有利于为继续研究建立坚实的研究平台，从而产生FDA批准的产品。

DESCRIPTION (provided by applicant): 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.