Sarm1 and neural regulation of bone

Sarm1 和骨的神经调节

基本信息

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
项目类别：
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

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

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项目摘要

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.

抽象的 SARM1（无菌α和TIR基序蛋白-1）是一种NADase酶，高度表达在神经系统。 SARM1酶用作代谢生物传感器，并响应于损伤，感染和氧化应激。根据2013年成千上万候选人的屏幕，SARM1是被确定为神经轴突变性的中央执行者。从那时起，SARM1也已显示通过调节MAPK信号传导和代谢物周转来调节神经功能。为此回应关键发现，SARM1抑制剂现在正在开发用于神经退行性的临床管理疾病。特异性 - 神经损伤，功能障碍和临床神经病都与骨折有关在潜水员条件下的风险和骨骼健康受损，包括脊髓损伤，厌食，化学疗法，多发性硬化症和糖尿病。但是，这些关系基础的分子机制仍然存在不清楚，限制了我们的治疗干预选择。最近，我们发现SARM1的淘汰赛防止糖尿病小鼠中的骨骼脆弱性。我们的中心假设是神经SARM1激活限制了骨骼形成，导致骨骼质量和力量降低。相反，我们假设有针对性的SARM1 抑制可用于简单地促进慢性SARM1激活状态的骨骼和神经健康，例如糖尿病。为了检验这一假设，我们将追求两个具体的目标。首先，我们将隔离 SARM1依赖性神经病在骨骼疾病的进展中。其次，我们将针对 SARM1在体内恢复骨骼健康。完成后，这项工作将定义连接神经的机制通过SARM1损害骨骼健康受损。我们还将确定SARM1抑制是否是一种策略可用于支持骨骼疾病环境中的骨形成。我们的长期目标是促进终身通过制定预防或逆转神经和骨损伤的策略，健康和健康衰老潜水疾病状态，从童年和青少年开始，并在整个生命周期内持续。