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

描述（由申请人提供）：胃肠道是独一无二的，因为它具有高度增殖的干细胞群，因此，对辐射引起的损伤的敏感性仅次于造血系统。辐射损伤最有害的影响之一是上皮通透性增加，可能促进细菌易位和败血症。辐照对全身和局部（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，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道黏膜免受高剂量辐射引起的损伤或促进其修复，其中包括角质细胞生长因子（KGF）。辐照后损伤的治疗目标是维持肠道黏膜干细胞和上皮细胞的活力，诱导其增殖和成熟。该应用的总体目标是确定辐射诱导肠道结构和功能改变的机制，并评估KGF和医疗管理在减轻全腹照射非人灵长类动物（NHP）模型中这些改变的功效。该应用有两个具体目的：1)确定NHP胃肠道中辐照诱导变化的动力学。我们将使用腹腔辐射模型，骨髓屏蔽，以限制骨髓抑制作用，以评估对肠道的特异性影响。综合和高度垂直的方法将评估辐射引起的形态和功能变化的全部范围，从照射时间开始，一直延伸到恢复期。这些研究将包括涉及粘膜屏障功能破坏和重建的免疫介导机制；2)确定KGF对辐照致NHP胃肠道病变的治疗效果。初步数据表明，KGF通过影响隐窝存活来防止辐射引起的屏障功能丧失。我们将在与Specific Aim 1平行的研究中确定辐照后KGF治疗的疗效。我们汇集了一群经验丰富的研究人员，他们在胃肠道生理学、辐射生物学和免疫学方面具有专业知识。这些实验旨在为潜在的产品开发计划提供支持性数据。强大的科学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，从而获得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.