Sarm1 and neural regulation of bone

Sarm1 和骨的神经调节

• 批准号: 10584348
• 负责人: Erica Lynn Scheller
• 金额: $ 42.98万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-13 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584348
• 关键词: ACTL6B gene; Adolescence; Anorexia; Biosensor; Bone Diseases; Bone Growth; Childhood; Chronic; Clinical; Clinical Management; Custom; Data; Diabetes Mellitus; Diabetic mouse; Disease; Enzymes; Functional disorder; Future; Goals; Health; High Fat Diet; Homeostasis; Impairment; Inflammation; Injury; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Knock-out; Knockout Mice; Link; Longevity; MAP Kinase Gene; Mediating; Mediator; Metabolic; Metabolic Diseases; Molecular; Multiple Sclerosis; N-terminal; NAD+ Nucleosidase; Natural regeneration; Nerve; Nervous System; Neurodegenerative Disorders; Neurons; Neuropathy; Neurophysiology - biologic function; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Osteogenesis; Outcome; Oxidative Stress; Pathway interactions; Peripheral; Peripheral Nervous System Diseases; Prevalence; Prevention; Prevention strategy; Preventive Medicine; Proteins; Regenerative Medicine; Regulation; Regulatory Pathway; Resistance; Role; Sensory; Signal Transduction; Spinal cord injury; Sterility; System; Testing; Therapeutic Intervention; Time; Virus; Work; afferent nerve; axonal degeneration; bone; bone cell; bone fragility; bone health; bone mass; bone strength; chemotherapy; conditional knockout; diabetic; fracture risk; healthy aging; in vivo; inhibitor; knockout animal; loss of function; mouse model; nerve damage; neural; neuroregulation; novel; prevent; response; response to injury; sarcopenia; skeletal; skeletal disorder; tool; treatment strategy; type I and type II diabetes

ABSTRACT Sarm1 (sterile α and TIR motif-containing protein-1) is a NADase enzyme that is highly expressed in the nervous system. The Sarm1 enzyme serves as a metabolic biosensor and is activated in response to injury, inflammation, and oxidative stress. Based on a screen of thousands of candidates in 2013, Sarm1 was identified as the central executioner of nerve axon degeneration. Since this time, Sarm1 has also been shown to modulate nerve function through regulation of MAPK signaling and metabolite turnover. In response to this pivotal discovery, Sarm1 inhibitors are now being developed for clinical management of neurodegenerative disease. Specific to bone - nerve damage, dysfunction and clinical neuropathy have all been related to fracture risk and impaired bone health in diverse conditions including spinal cord injury, anorexia, chemotherapy, multiple sclerosis and diabetes. However, the molecular mechanisms underlying these relationships remain unclear, limiting our options for therapeutic intervention. Recently, we discovered that knockout of Sarm1 prevents bone fragility in diabetic mice. Our central hypothesis is that neural Sarm1 activation restricts bone formation, leading to decreased bone mass and strength. Conversely, we hypothesize that targeted Sarm1 inhibition can be used to simultaneously promote bone and nerve health in states of chronic Sarm1 activation, such as diabetes. To test this hypothesis, we will pursue two specific aims. First, we will isolate the role of Sarm1-dependent neuropathy in the progression of skeletal disease. Second, we will target the function of Sarm1 to restore bone health in vivo. When complete, this work will define the mechanisms linking nerve damage to impaired bone health through Sarm1. We will also determine if Sarm1 inhibition is a strategy that can be used to support bone formation in settings of skeletal disease. Our long-term goal is to promote lifelong health and healthy aging by developing strategies to prevent or to reverse nerve and bone damage across diverse disease states, beginning in childhood and adolescence and continuing throughout the lifespan.

摘要 SARM 1（含不育α和TIR基序的蛋白-1）是一种NAD酶，在大肠杆菌中高度表达。 神经系统Sarm 1酶作为一种代谢生物传感器，并响应于 损伤、炎症和氧化应激。根据2013年对数千名候选人的筛选，Sarm 1是 被认为是神经轴突退化的中央刽子手。此后，Sarm 1也被证明是 通过调节MAPK信号和代谢物周转来调节神经功能。针对这一 关键的发现，Sarm 1抑制剂现在正在开发用于神经退行性疾病的临床管理。 疾病具体到骨神经损伤、功能障碍和临床神经病变都与骨折有关 风险和受损的骨骼健康在不同的条件，包括脊髓损伤，厌食症，化疗， 多发性硬化症和糖尿病然而，这些关系背后的分子机制仍然存在 不清楚，限制了我们治疗干预的选择。最近，我们发现， 预防糖尿病小鼠的骨脆性。我们的中心假设是，神经Sarm 1激活限制骨 形成，导致骨量和强度下降。相反，我们假设靶向Sarm 1 抑制可用于在慢性Sarm 1激活状态下同时促进骨和神经健康， 例如糖尿病。为了检验这个假设，我们将追求两个具体目标。首先，我们将隔离 骨骼疾病进展中的sarm 1依赖性神经病变。第二，我们将针对 sarm 1在体内恢复骨骼健康。完成后，这项工作将确定连接神经的机制 通过SARM 1损害受损的骨骼健康。我们还将确定抑制Sarm 1是否是一种策略， 可用于支持骨骼疾病中的骨形成。我们的长期目标是促进终身 健康和健康老龄化的发展战略，以防止或扭转神经和骨骼损伤， 不同的疾病状态，从儿童和青少年开始，并持续整个生命周期。