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）： 创伤性脑损伤 (TBI) 是一种因外力对大脑造成的损伤，每年都会导致退伍军人和普通人群大量死亡和永久性残疾，是最常见的神经性脑损伤。虽然头部原发性损伤对最初几小时和几天内发生的病理生理和神经化学事件的后果和机制正在进行广泛的研究，但人们知之甚少。从长远来看TBI 对通过垂体进行下丘脑控制的远程器官的影响 在这个优点审查提案中，我们基于以下基本原理选择研究 TBI 对骨骼系统的影响。一个新兴的研究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。下丘脑分泌生长激素释放激素 (GHRH)，作用于脑下垂体，调节生长激素 (GH) 的产生，生长激素是调节骨骼代谢的重要激素。据估计，30-50% 的 TBI 患者患有垂体功能减退症。基于下丘脑核细胞在骨的神经（内分泌）调节中的重要作用，最近的研究证明了骨量瘦素和神经肽的中枢控制作用。 可以预见，大脑损伤将对控制骨骼生长和维持的调节分子产生严重影响。基于上述原理，我们建议在本研究中检验以下假设：1）TBI，即使在其过程中。较温和的形式，对骨骼生长和维持以及骨骼响应损伤修复受损组织的能力产生持久的负面影响 2) TBI 对骨形成 (BF) 的减弱作用部分是通过下调骨形成 (BF) 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性轻度 TBI 小鼠模型，该模型利用体重下降方法来创建。我们建议使用轻度 TBI 模型，因为美国每年报告的 170 万例 TBI 病例中约有 85% 属于轻度病例。轻度 TBI 小鼠模型在骨骼研究中的有用性 为了确定轻度 TBI 是否对骨骼再生损伤的能力产生负面影响，我们将诱导标准闭合股骨骨折，并使用显微 CT、组织学和评估修复。为了评估 GH/IGF-I 轴的作用，我们将确定 TBI 小鼠中 GH/IGF-I 水平的变化是否是由下丘脑 GHRH 表达减少引起的。为了确定 GH/IGF 产生减少是否会导致小鼠 BF 受损，我们将给 TBI 小鼠施用 GH，并评估 GH 替代是否可以挽救 TBI 诱导的 BF 和骨再生变化。我们还将确定 TBI 和骨骼卸载是否会导致比单独使用任何一种情况更大的 BF 缺陷，因为 TBI 患者是受伤后立即长期卧床不起，并且由于骨骼卸载通过抑制 IGF-I 信号通路的激活而诱导对 IGF-I 的抵抗，我们将使用尾悬后肢抬高模型对 TBI 和对照小鼠进行骨骼卸载或正常加载。并通过显微 CT、组织形态计量学或基因表达分析评估骨骼参数。我们相信，我们对所提出假设的成功证实将有助于开发新的治疗策略，以促进 TBI 患者的长期健康。