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

描述（由申请方提供）：胃肠道是独特的，因为其具有高度增殖的干细胞群，因此，在对辐射诱导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，这可能促进细菌移位和脓毒症。辐射对全身和局部（肠道）免疫反应的影响，这在粘膜屏障功能的调节中起着关键作用，是拟议研究的新组成部分。有一些生长因子可以保护肠粘膜免受高剂量辐射诱导的损伤或促进其恢复，包括角质细胞生长因子（KGF）。辐射后损伤的治疗目标是维持活力并诱导肠粘膜的干细胞和上皮细胞的增殖和成熟。本申请的总体目标是确定辐射诱导的肠道结构和功能改变的机制，并评估KGF和医学管理在全腹部辐射的非人灵长类动物（NHP）模型中减轻这些改变的功效。该应用具有两个具体目的：1）确定NHP胃肠道中辐射诱导的变化的动力学。我们将使用仅腹部照射的模型，骨髓屏蔽以限制骨髓抑制作用，以评估对肠道的特定影响。这种高度垂直的综合办法将评价从受照之时起直至恢复期内辐射引起的形态和功能变化的全部范围。这些研究将包括参与粘膜屏障功能破坏和重建的免疫介导机制; 2）确定KGF对辐射诱导的NHP胃肠道变化的治疗功效。初步数据显示，KGF通过影响隐窝存活来防止辐射诱导的屏障功能丧失。我们将在平行研究中确定照射后KGF治疗的疗效，以达到特定目标1。我们已经召集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性数据。强大的科学环境和独特的机构资源有利于建立一个坚实的研究平台，以继续研究，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.