Impact of Mild TBI on Bone Formation

轻度 TBI 对骨形成的影响

• 批准号: 9519699
• 负责人: SUBBURAMAN MOHAN
• 金额: --
• 依托单位: VA LOMA LINDA HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9519699
• 关键词: Acute; Address; Annual Reports; Area; Attenuated; Bed rest; Binding Proteins; Body Composition; Bone Growth; Bone Regeneration; Bone Resorption; Bone remodeling; Bone structure; Brain; Brain region; Cell Nucleus; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Closed head injuries; Development; Diagnosis; Down-Regulation; Drops; Endocrine system; Event; Facilities and Administrative Costs; Femoral Fractures; Fracture; Functional disorder; Future; Gene Expression; Gene Expression Profiling; General Population; Growth; Head; Health; Histology; Hormones; Hour; Hypopituitarism; Hypothalamic structure; Immunohistochemistry; Impairment; Incidence; Injury; Insulin-Like Growth Factor I; Lead; Leptin; Life; Limb structure; Liver; Maintenance; Measurement; Measures; Mediating; Medical Care Costs; Metabolic; Metabolism; Methods; Modeling; Mus; Natural regeneration; Nervous system structure; Neurologic; Neuropeptides; Neurosecretory Systems; Organ; Osteogenesis; Osteoporosis; Outcome; Pathogenesis; Patients; Personal Satisfaction; Phase; Pituitary Gland; Population; Preventive therapy; Production; Productivity; Public Health; Quality of life; Regulation; Research; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Pathway; Signaling Molecule; Skeletal system; Skeleton; Somatomedins; Somatotropin; Somatotropin-Releasing Hormone; Spinal cord injury; Stroke; Study models; TBI Patients; Tail Suspension; Testing; Time; Tissues; Translational Research; Traumatic Brain Injury; United States; Veterans; Weight; base; bone; bone cell; bone healing; bone loss; bone mass; disability; hormone therapy; human model; improved; microCT; mild traumatic brain injury; mind control; mouse model; neurochemistry; neuroregulation; neurotransmission; novel; novel therapeutic intervention; public health relevance; relating to nervous system; repaired; response; response to injury; skeletal; skeletal regeneration; skeletal unloading; therapy development

 DESCRIPTION (provided by applicant): Traumatic brain injury (TBI), which involves damage to the brain from an external force, contributes to a substantial number of deaths and cases of permanent disability both in the Veteran population as well as in the general population each year. TBI is the most common neurological diagnosis in the U.S. and has been identified as a serious public health problem. While the consequences and mechanisms of primary injury to the head on the pathophysiological and neurochemical events that occur during the course of initial hours and days are being extensively investigated, little is known on the long term consequence of TBI on remote organs that are under hypothalamic control via the pituitary. In this merit review proposal, we have chosen to study the TBI effect on the skeletal system based on the following rationale. Recently, the discovery of bone regulation by neural signals represents an emerging area of study that is identifying novel regulatory axes between the nervous system and bone cells. In this regard, it is well known that the hypothalamic region of the brain controls the endocrine system via the pituitary. Notably, the hypothalamus secretes growth hormone releasing hormone (GHRH) which acts on the pituitary gland to regulate production of growth hormone (GH), an important hormone that regulates skeletal metabolism. It is estimated that 30-50% of TBI patients suffer from hypopituitarism. Besides, recent studies demonstrate an important role for central control of bone mass involving leptins and neuropeptides. Based on the important role for cells of the hypothalamic nuclei in the neuro (endo)crine regulation of bone remodeling, it is predictable that injury to the brain will have a severe impact on the regulatory molecules that control skeletal growth and maintenance. Based on the above rationale, we propose to test the following hypotheses in this study: 1) TBI, even in its milder form, exerts lon lasting negative effects on bone growth and maintenance and the ability of skeleton to repair the damaged tissue in response to injury. 2) The attenuating effects of TBI on bone formation (BF) are mediated in part via down regulation of the GH/insulin-like growth factor-I axis. 3) TBI exaggerates the negative effects of skeletal unloading on BF. To test these hypotheses, we will use a recently established mouse model of human repetitive mild TBI which utilizes the weight drop method to create a closed head injury. We have proposed to use the mild TBI model as approximately 85% of the 1.7 million cases of TBI reported annually in the United State represent mild cases. In our preliminary studies, we have validated the usefulness of the mild TBI mouse model for studies on bone. In order to determine if mild TBI exerts negative effects on the ability of the skeleton to regenerate injuries, we will induce a standard closed femoral fracture and evaluate repair using micro-CT, histology and gene expression end points. To evaluate the role of the GH/IGF-I axis, we will determine if changes in GH/IGF-I levels in the TBI mice are caused by reduced expression of GHRH in the hypothalamus by immunohistochemistry. To determine if reduced GH/IGF production contributes to impaired BF in mice, we will administer GH to TBI mice and evaluate if TBI-induced changes in BF and bone regeneration are rescued by GH replacement. We will utilize a GH deficient lit/lit mouse model to evaluate the role of GH in TBI-induced bone loss. We will also determine if TBI and skeletal unloading lead to greater BF deficits than either condition alone since TBI patients are bedridden for extended periods immediately post injury and since skeletal unloading induces resistance to IGF-I by inhibiting activation of the IGF-I signaling pathways. We will subject TBI and control mice to skeletal unloading using the tail suspension hind limb elevation model or to normal loading and evaluate skeletal parameters by micro-CT, histomorphometry or gene expression analyses. We believe that our successful confirmation of proposed hypotheses will lead to development of new therapeutic strategies to promote long-term health of TBI patients.

 描述（由申请人提供）： 脑外伤（TBI）涉及外部力量损害大脑的损害，每年在退伍军人人口以及一般人口中都会导致次要的死亡和永久残疾病例。 TBI是美国最常见的神经系统诊断，已被确定为严重的公共卫生问题。尽管在初始数小时和几天内发生的病理生理和神经化学事件的主要损伤的后果和机制正在广泛研究中，但对TBI对偏远甲丘脑控制的偏远器官的长期后果知之甚少。在这项优点审查提案中，我们选择根据以下理由研究对骨骼系统的TBI效应。最近，通过神经信号对骨调节的发现代表了一个新的研究领域，该领域正在识别神经系统和骨细胞之间的新调节轴。在这方面，众所周知，大脑的下丘脑区域通过垂体控制内分泌系统。值得注意的是，下丘脑的秘密会释放骑马（GHRH），该骑马（GHRH）作用于垂体上，以调节生长马烯（GH）的产生，这是一种调节骨骼代谢的重要骑士。据估计，有30％至50％的TBI患者患有垂体不足。此外，最近的研究表明，涉及瘦素和神经肽的骨骼质量控制中心控制着重要作用。基于下丘脑核细胞在神经（内托）骨骼调节中的重要作用 重塑，可以预见的是，对大脑的损伤将对控制骨骼生长和维持的调节分子产生严重影响。基于上述基本原理，我们建议在本研究中检验以下假设：1）TBI，即使以米勒的形式，也会对lon产生持久的负面影响，对骨骼生长和维持以及骨骼对造成伤害的损害组织的修复组织的能力。 2）TBI对骨形成（BF）的衰减作用是通过调节GH/胰岛素样生长因子-I轴的部分介导的。 3）TBI夸大了骨骼卸载对BF的负面影响。为了检验这些假设，我们将使用最近建立的人类重复轻度TBI的小鼠模型，该模型利用重量下降方法来产生闭合的头部损伤。我们建议使用轻度TBI模型，因为在美国每年报告的170万例TBI病例中，约有85％代表轻度病例。在我们的初步研究中，我们验证了轻度TBI小鼠模型对骨骼研究的有用性。为了确定轻度TBI是否对骨架再生损伤的能力产生负面影响，我们将诱发标准的闭合股骨断裂，并使用微CT，组织学和基因表达终点评估修复。为了评估GH/IGF-1轴的作用，我们将确定TBI小鼠中GH/IGF-1水平的变化是否是由免疫组织化学下下丘脑中GHRH表达降低引起的。为了确定降低的GH/IGF产生是否有助于小鼠的BF受损，我们将对TBI小鼠进行GH施用，并评估TBI诱导的BF和骨再生的变化是否通过GH替代作出反应。我们将利用GH缺乏的小鼠模型来评估GH在TBI诱导的骨质流失中的作用。我们还将确定TBI和骨骼卸载是否会导致BF更大的BF，因为TBI患者在受伤后立即卧床不起，并且由于骨骼卸载会通过抑制IGF-I信号通路的激活而影响IGF-I的耐药性。我们将使用Micro-CT，Histormorphormetry或Gene表达分析进行尾悬浮液后肢高程模型或正常负载和对照骨骼参数进行TBI和对照小鼠进行骨骼卸载。我们认为，我们成功确认提出的假设将导致发展新的治疗策略，以促进TBI患者的长期健康。