Neural regulation of skeletal biology and periodontal disease progression in type

骨骼生物学的神经调节和牙周病进展的类型

基本信息

批准号：
9260998
负责人：
Erica Lynn Scheller
金额：
$ 24.9万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9260998
关键词：
12 year old Adipose tissue Aging Anorexia Biology Bone Density Bone Marrow Bone Regeneration Chemicals Chile Clinical Complex Coupling Cues Data Denervation Dental Hygiene Detection Development Diabetes Mellitus Disease Disease Outcome Disease Progression Evolution Fatty acid glycerol esters Functional disorder Goals Grant Health Hour Image Inflammation Inflammatory Response Injection of therapeutic agent Insulin Insulin-Dependent Diabetes Mellitus Intervention Leptin Link Lipolysis Maintenance Marrow Mediating Mentors Metabolism Methods Modeling Mouth Diseases Nerve Neuronal Dysfunction Neuropathy Neuropeptides Norepinephrine Osteoclasts Osteopenia Osteoporosis Outcome Patients Periodontal Diseases Periodontitis Phase Prevalence Prevention strategy Research Risk Factors Rodent Rodent Model Sensory Sensory Ganglia Severities Skeletal bone Skeleton Spinal Cord Streptozocin Substance P Sympathetic Ganglia Testing Training Transgenic Organisms Travel United States Universities Vasoconstrictor Agents Vasodilator Agents Work afferent nerve bone bone health bone loss diabetic diabetic patient in vivo nerve supply neuroregulation neurotransmission novel older patient osteogenic postsynaptic neurons presynaptic neurons programs relating to nervous system skeletal treatment strategy vasoconstriction

项目摘要

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.

描述（由申请人提供）：糖尿病是牙周病发生的主要危险因素，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 万患有严重牙周炎。人们普遍认为牙周病的严重程度与炎症的存在相关。然而，炎症并不能完全解释牙周病的快速进展、全身骨骼骨质流失和骨髓脂肪堆积，这些现象可以在牙菌斑水平低且口腔卫生良好的年轻胰岛素依赖型糖尿病患者中观察到。因此，其他机制可能正在介导骨质流失和糖尿病的耦合。自 1967 年以来，人们多次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。骨骼和牙周复合体高度神经支配，神经功能的局部变化能够调节骨微环境和覆盖的炎症反应。然而，尽管有大量相关证据表明糖尿病中的神经病变和牙周病之间存在联系，但局部神经病变导致糖尿病中骨质流失、骨髓脂肪堆积和牙周病发展的能力仍未得到探索。我们的中心假设是，在糖尿病中，感觉去神经支配和骨骼中感觉神经肽的消耗会增强血管收缩和骨髓脂肪的积累，同时限制骨再生。这些变化将使糖尿病患者容易出现骨质减少和牙周病的进展。如果目标神经功能障碍被确定为骨质流失和牙周病的根本原因，那么治疗和预防策略将有可能发生重大演变。我们将在链脲佐菌素的啮齿动物模型中检验我们的假设诱导胰岛素依赖性糖尿病，有或没有神经信号传导的化学、物理或转基因抑制。当这项工作完成后，我们期望确定骨骼代谢的神经调节因子，并确定这些发现与糖尿病相关骨质流失和牙周病进展的体内相关性。这些结果预计将产生广泛的积极影响，因为骨骼的神经调节与骨质流失和骨髓脂肪积累相关的其他疾病有关，包括骨质疏松症、衰老、性腺功能障碍和厌食症。