Aging: Effects on Infection, Inflammation and Disease

描述（由申请人提供）：本提案是肯塔基大学、马里兰大学和国家衰老研究所神经科学实验室营养与分子生理学单元的合作提交。拟议的研究将建立在NIA从限制卡路里和正常饮食的恒河猴身上获得的现有数据基础上，并将为我们对限制卡路里动物炎症反应改变的初步观察提供生物学基础。本研究的重点是利用口腔作为模型系统来研究衰老对宿主-细菌相互作用的影响，因为它们与粘膜表面的微生物定植、炎症/免疫反应的诱导和调节以及这些相互作用可能导致的宿主组织的病理破坏有关。本研究的目的是测试以下对比的科学假设：(a)热量限制（CR）通过影响微生物斑块的致病性来减少临床炎症，这些变化是由于致病性和非致病性微生物的比例和/或克隆类型的变化；(b) CR通过增加促炎分子释放，影响先天免疫机制，从而改变炎症的临床表现；和/或(c) CR通过调节抗炎分子的释放而影响先天免疫机制，从而改变炎症的临床表现。目的1是一项横断面回顾性研究，以确定长期热量限制饮食对慢性和非慢性恒河猴自然发生的炎症性牙周病进展的影响。研究人员将评估CR对临床炎症、粘膜表面微生物定植以及促炎和抗炎机制的影响。目的2是一项纵向前瞻性研究，旨在确定热量限制饮食对实验性结扎性牙周炎的临床、微生物和宿主反应的影响，这些反应在相同的CR和非CR恒河猴中观察到。这些研究将提供CR对粘膜部位临床、微生物学和炎症变化动力学的影响信息。这些研究的意义在于我们能够使用非人类灵长类动物和口腔来评估CR作为调节感染，炎症和炎症性疾病的手段的功效。长期的影响是，饮食控制可以被视为一种有效的公共保健措施，以改善整个人口的口腔和整体健康和福利。

DESCRIPTION (provided by applicant): This proposal is a collaborative submission from the University of Kentucky, the University of Maryland, and the Nutritional and Molecular Physiology Unit of the Laboratory of Neurosciences of the National Institute on Aging. The proposed studies will build on existing data obtained from Rhesus monkeys being maintained on calorie restricted and normal diets by the NIA, and will provide a biologic basis for our preliminary observations of altered inflammatory responses in calorie restricted animals. This proposal focuses on utilizing the oral cavity as a model system to examine the impact of aging on host-bacterial interactions as they relate to microbial colonization of mucosal surfaces, the induction and regulation of inflammatory/immune responses, and the pathologic destruction of host tissues that may result from these interactions. The aims of this study will test the following contrasting scientific hypotheses: (a) that caloric restriction (CR) reduces clinical inflammation by affecting the pathogenicity of microbial plaque, and that these changes are due to shifts in the proportions and/or clonal type of the constituent pathogenic and non-pathogenic microorganisms; (b) that CR alters the clinical manifestation of inflammation through an effect on innate immune mechanisms through increased pro-inflammatory molecule release; and/or (c) that CR alters the clinical manifestation of inflammation through an effect on innate immune mechanisms by regulating the release of anti-inflammatory molecules. Aim 1 is a cross-sectional retrospective study to determine the effects of a long-term calorie restricted diet on the progression of naturally occurring inflammatory periodontal disease in CR and non-CR Rhesus monkeys. The effects of CR on clinical inflammation, microbial colonization of mucosal surfaces, and pro-inflammatory and anti-inflammatory mechanisms will be evaluated. Aim 2 is a longitudinal prospective study to determine the effects of a calorie-restricted diet on the clinical, microbiological, and host responses observed during experimental ligature-induced periodontitis in the same CR and non-CR Rhesus monkeys. These studies will provide information on the effects of CR on the kinetics of clinical, microbiologic, and inflammatory changes at mucosal sites. The significance of these studies lies in our capability to use nonhuman primates and the oral cavity to evaluate the efficacy of CR as a means to regulate infection, inflammation, and inflammatory disease. The long-term implications are that diet control may be considered as an effective public healthcare measure for improving the oral and general health and welfare of the population as a whole.