权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Interrogating adrenal dysfunction to prevent muscle wasting after acute spinal cord injury

检查肾上腺功能障碍以防止急性脊髓损伤后肌肉萎缩

基本信息

批准号：
10269923
负责人：
Markus E. Harrigan
金额：
$ 3.22万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2022-05-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10269923
关键词：
Ablation Acute Adrenal Gland Hyperfunction Adrenal Glands Adrenalectomy Adult Affect American Attenuated Autologous Biological Assay Cardiovascular system Cessation of life Chest Clinical Collaborations Communication Data Decentralization Denervation Development Doctor of Philosophy Endocrine Environment Enzyme-Linked Immunosorbent Assay Experimental Designs Exposure to FBXO32 gene Foundations Frequencies Functional disorder Gene Expression Gene Proteins Glucocorticoid Receptor Glucocorticoids Goals Hormones Human Intervention Knock-out Knowledge Measures Mediator of activation protein Metabolic Mifepristone Mixed Function Oxygenases Morbidity - disease rate Muscle Muscle function Muscular Atrophy Neurosecretory Systems Outcome Measure Paralysed Pathologic Pathology Pharmacology Phase Pilot Projects Quality of life Recovery Recovery of Function Reflex action Rehabilitation therapy Research Research Personnel Rodent Rodent Model Severities Signal Transduction Spinal Spinal cord injury Spinal cord injury patients Steroids Supervision Sympathectomy Technical Expertise Testing Thoracic spinal cord structure Time Training Transplantation Weight acute care base career conditional knockout dexamethasone suppression test disability experimental study functional disability hypothalamic-pituitary-adrenal axis in vivo insight mortality muscle form nerve supply neuromuscular novel pressure prevent programs protein expression respiratory skills wasting

项目摘要

SUMMARY Traumatic spinal cord injury (SCI) is a devastating condition that affects ~18,000 Americans annually, resulting in death or a lifetime of severe disability. Early muscle wasting is an endemic consequence of SCI that contributes to mortality, impaired functional recovery and the development of secondary complications. Current interventions are not started until after considerable muscle wasting has already occurred during acute care and are minimally effective. To reduce mortality and maximize quality of life, mechanism-based interventions are needed to protect muscle and prevent wasting during the critical acute period ‘bridging’ between SCI and rehabilitation. Though denervation and inactivity of paralyzed muscles are common explanations for muscle wasting, they cannot explain the wasting of non-paralyzed muscles that occurs early after SCI. Interestingly, high thoracic level SCI concurrently exacerbates acute hypercortisolism and systemic muscle wasting, compared to low thoracic level SCI; Transient hypercortisolism during acute low thoracic SCI corresponds with transient non-paralyzed muscle wasting, whereas progressive hypercortisolism corresponds with enduring non-paralyzed muscle wasting during acute high thoracic SCI. SCI level-dependent hypercortisolism represents a systemic candidate signal exacerbating systemic muscle wasting since glucocorticoids potently induce muscle wasting. This research will investigate the cause of acute SCI level-dependent hypercortisolism and determine whether protecting muscle from glucocorticoids attenuates systemic muscle wasting during acute high thoracic level SCI. Based on pilot data, the investigators aim to determine whether SCI level-dependent acute hypercortisolism results from skewed sympathetic control over adrenal function. Hypothalamic-pituitary-adrenal (HPA)-axis hormones, HPA- axis function, and adrenal glucocorticoid synthesis during the acute phase of high and low thoracic SCI will be profiled. Then, it will be investigated whether shielding the adrenal glands from spinal sympathetic reflex activity by sympathetic denervation attenuates SCI level-dependent hypercortisolism. Subsequently, the investigators will determine whether preventing muscle exposure to glucocorticoids through pharmacological glucocorticoid receptor (GR) antagonism or knockout of muscle GR attenuates SCI level-dependent muscle wasting severity, as determined by measures of muscle mass, muscle function, muscle composition and gene/protein expression quantification of muscle wasting mediators. This research will be conducted by an MD/PhD candidate under the supervision of 2 leaders in the field of SCI research and in collaboration with 3 neuromuscular experts. The MD/PhD program is well established, and the institutional environment is exceptionally strong in SCI, myology and endocrine research. The training plan consists of opportunities to develop the foundational scientific knowledge, independence, technical expertise, communication skills, and creative and rigorous experimental design necessary to pursue an independent research career in the field of SCI.

总结