Neural regulation of skeletal biology and periodontal disease progression in type

描述（由申请人提供）：糖尿病是牙周病发展的主要危险因素，自1980年以来患病率增加了400%。在美国2500万糖尿病患者中，估计有750万人患有严重的牙周炎。人们普遍认为牙周病的严重程度与炎症的存在有关。然而，炎症并不能完全解释牙周病的快速进展、全身性骨质流失和骨髓脂肪堆积，这些在斑块水平低、口腔卫生良好的年轻胰岛素依赖型糖尿病患者中可以观察到。因此，可能有其他机制介导了骨质流失和糖尿病的耦合。自1967年以来，已经反复注意到临床神经病变与糖尿病患者牙周病的患病率和严重程度相关。骨骼和牙周复合体是高度神经支配的，神经功能的局部变化具有调节骨微环境和炎症反应的能力。然而，尽管有重要的相关证据表明糖尿病患者的神经病变与牙周病有关，但局部神经病变改变对糖尿病患者骨质流失、骨髓脂肪积累和牙周病发展的影响仍未得到证实。我们的中心假设是，在糖尿病中，骨骼中感觉神经肽的去神经支配和耗竭增强了血管收缩和骨髓脂肪的积累，同时限制了骨再生。这些变化会使糖尿病患者易患骨质减少和牙周病。如果靶向神经功能障碍被确定为骨质流失和牙周病的潜在原因，治疗和预防策略将有可能发生重大变化。我们将在链脲佐菌素的啮齿动物模型中检验我们的假设

DESCRIPTION (provided by applicant): Diabetes, a major risk factor for development of periodontal disease, has increased in prevalence by 400% since 1980. Of the 25 million diabetic patients in the United States, it is estimated that 7.5 million have severe periodontitis. It is generally accepted that the severity of periodontal disease is correlated with the presence of inflammation. However, inflammation fails to completely explain the rapid progression of periodontal disease, generalized skeletal bone loss, and marrow fat accumulation that can be observed in young insulin-dependent diabetics with low plaque levels and good oral hygiene. Therefore, it is likely that other mechanisms are mediating the coupling of bone loss and diabetes. Since 1967 it has been repeatedly noted that clinical neuropathy is correlated with both the prevalence and severity of periodontal disease in diabetic patients. The skeleton and periodontal complex are highly innervated and local changes in nerve function have the capacity to regulate both the bone microenvironment and the overlying inflammatory response. However, despite significant correlative evidence linking neuropathy and periodontal disease in diabetes, the ability of local neuropathic change to contribute to bone loss, marrow fat accumulation and periodontal disease development in diabetes remains unexplored. Our central hypothesis is that in diabetes, sensory denervation and depletion of sensory neuropeptides in the skeleton enhances vasoconstriction and accumulation of marrow fat while limiting bone regeneration. These changes would predispose diabetic patients to development of osteopenia and progression of periodontal disease. If targeted neural dysfunction is identified as an underlying cause of bone loss and periodontal disease, treatment and prevention strategies will have the potential for significant evolution. We will test our hypothesis in rodent models of streptozotocin induced insulin-dependent diabetes with or without chemical, physical or transgenic inhibition of neural signaling. When this work is completed we expect to identify neural regulators of skeletal metabolism and determine the in vivo relevance of these findings to progression of diabetes-associated bone loss and periodontal disease. These outcomes are expected to have a broad positive impact because neural regulation of the skeleton is relevant to other conditions associated with bone loss and marrow fat accumulation including osteoporosis, aging, gonadal dysfunction and anorexia.