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：
9272878
负责人：
Erica Lynn Scheller
金额：
$ 24.65万
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/9272878
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 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 Neural Inhibition 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 osteogenic postsynaptic neurons presynaptic neurons programs public health relevance 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）：糖尿病是牙周疾病发展的主要危险因素，自1980年以来的患病率增加了400％。在美国的2500万糖尿病患者中，据估计，有750万的牙周炎患有严重的牙周炎。人们普遍认为，牙周疾病的严重程度与炎症的存在相关。然而，炎症无法完全解释牙周疾病，广义骨骼骨质流失和骨髓脂肪积累的快速进展，这些进展可以在年轻的胰岛素依赖性糖尿病患者中观察到，斑块水平低和口腔良好。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，人们反复注意到，临床神经病与糖尿病患者的牙周疾病的患病率和严重程度相关。骨骼和牙周络合物高度支配，神经功能的局部变化具有调节骨微环境和上覆的炎症反应的能力。然而，尽管糖尿病中神经病和牙周疾病联系起来的明显相关证据，但局部神经性变化有助于骨质流失，骨髓脂肪的积累和糖尿病牙周疾病的发展的能力仍未得到探索。我们的中心假设是，在糖尿病中，骨骼中感觉神经肽的感觉神经肽的耗竭可增强骨髓脂肪的血管收缩和积累，同时限制骨骼再生。这些变化将使糖尿病患者易患骨质减少症的发展和牙周疾病的进展。如果将靶向的神经功能障碍确定为骨质流失和牙周疾病的根本原因，则治疗和预防策略将有可能发生重大进化。我们将在链霉菌素的啮齿动物模型中检验我们的假设诱导的胰岛素依赖性糖尿病，有或没有化学，物理或转基因抑制神经信号传导。完成这项工作后，我们期望鉴定骨骼代谢的神经调节剂，并确定这些发现与糖尿病相关骨质流失和牙周疾病的进展的体内相关性。这些结果有望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有关的其他疾病有关，包括骨质疏松症，衰老，性腺功能障碍和厌食症。