Etiology of musculoskeletal maladies in NF1

NF1 肌肉骨骼疾病的病因学

基本信息

批准号：
10594471
负责人：
Florent Elefteriou
金额：
$ 35.2万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10594471
关键词：
Address Adult Affect Alkaline Phosphatase Amputation Behavior Bone Regeneration Bystander Effect Cancer Etiology Cell Lineage Cells Child Chondrocytes Chronic Clinical Management Compensation Data Set Defect Diphosphates Disease Etiology Exhibits Exposure to Fracture Genetic Induction Homeostasis Implant In Vitro Induced Mutation Leg Macrophage Malignant - descriptor Malignant Neoplasms Mesenchymal Mesenchymal Stem Cells Modeling Mus Muscle Muscle Cells Muscle Weakness Muscle function Muscular Atrophy Musculoskeletal Mutate Mutation Myoblasts NF1 gene Natural regeneration Neurofibromatosis 1 Orthopedics Osteoblasts Osteoclasts Osteogenesis Pain Pathway interactions Patients Pharmaceutical Preparations Phenotype Physiologic calcification Population Predisposition Preventive treatment Process Proliferating Property Pseudarthrosis Quality of life RNA Refractory Repeat Surgery Replacement Therapy Reporting Research Series Signal Pathway Signal Transduction Skeletal system Skeleton Somatic Mutation Therapeutic Tissues Work bone bone cell bone fragility bone healing bone mass bone repair cell suicide clinically relevant cost healing improved in vivo loss of function mechanical properties mouse model muscle form muscular structure muscular system osteogenic osteoprogenitor cell paracrine pharmacologic prevent reduced muscle mass repair function senescence targeted treatment therapeutic target tibia

项目摘要

Project Summary/Abstract Children with Neurofibromatosis Type 1 (NF1) are predisposed to cancer but can also present with unilateral bowing of the tibia that often progresses to fracture. Unlike the robust bone healing of most children, bone healing in these patients fails, leading to invasive and repeated surgeries, and often amputation of the leg. Research focused on identifying the cause of this refractory bone healing revealed that Nf1 deficiency in bone mesenchymal progenitors blunts their osteogenic potential and triggers chronic and uncontrolled RAS/ERK signaling, although blocking this pathway failed to rescue osteoprogenitor differentiation and the delayed bone healing of mice lacking Nf1 is osteoprogenitors. It has now become clear that multiple signaling pathways and compensatory mechanisms are involved in the abnormal differentiation of Nf1- null osteoprogenitors, and that targeting them to promote bone union in children with NF1 will be very challenging. This proposal steers away from this strategy, thanks to the observation of early senescence in Nf1-null osteoprogenitors, which should make them sensitive to “senolytic” drugs. Our hypothesis is thus that eliminating Nf1-null osteoprogenitors - rather than correcting their multiple defects – with senolytics will promote bone union in children with NF1 pseudarthrosis. We propose to determine if clearance of Nf1-null senescent osteoprogenitors, genetically or pharmacologically, improves the poor healing potential of mice lacking Nf1 in osteoprogenitors, and whether the senescence associated secretory phenotype (SASP) from these cells alters the behavior of lineages contributing to bone repair. A second major premise of this work is the observation that mice deficient for Nf1 selectively in adult osteoprogenitors lose muscle mass. This finding and other in vitro and in vivo results led us to challenge the current view of a muscle-intrinsic defect and to address the hypothesis that bone-derived factor(s) from Nf1-null osteoprogenitors contribute to the muscle weakness observed in children with NF1, which could also be alleviated by the clearance of Nf1-null osteoprogenitors with senolytics. Overall, this work has the potential to improve the clinical management of NF1 pseudarthrosis with a strategy that will pharmacologically clear faulty Nf1-null osteoprogenitors and relieve their inhibitory influence on other cells contributing to bone repair, thus restoring robust bone regeneration. Mechanistically, this study may support senescence in Nf1-null osteoprogenitors as a mechanism to prevent the spread of RAS-induced mutational damage and preclude potential malignant transformation at the cost of a deleterious bystander effect on bone repair and muscle function.

项目摘要/摘要神经纤维瘤病1型（NF1）的儿童容易患癌症，但也可以存在随着胫骨的单侧鞠躬，通常会骨折。与健壮的骨头不同大多数儿童的康复，这些患者的骨骼康复失败，导致侵入性并重复手术，通常是腿的截肢。研究重点是确定原因难治性的骨骼愈合表明，骨间充质祖细胞中的NF1缺乏率它们的成骨潜力并触发慢性和不受控制的RAS/ERK信号传导，但是阻止这一途径无法挽救骨化剂的分化和延迟的骨骼缺乏NF1的小鼠的愈合是破骨剂。现在已经很清楚多次信号途径和代偿机制与NF1-的异常分化有关无效的骨化剂，针对它们在NF1儿童中促进骨骼联合的目标是非常挑战。该提议窃取了该策略，感谢您的观察 NF1-NULL骨基因生成剂中的早期感受，这应该使其对“鼻溶剂”敏感毒品。因此，我们的假设是消除NF1 -NULL骨基因生成剂 - 而不是纠正它们的多重缺陷 - 塞溶剂将促进NF1儿童的骨结合伪关。我们建议确定NF1-NULL SENSCENT OSEPEREGERITOR的清除率是否从遗传学或药理上，提高了缺乏NF1的小鼠的愈合潜力差骨基因生成剂，以及感应相关的秘密表型（SASP）是否来自这些细胞改变了有助于骨修复的谱系行为。第二个重点这项工作的观察结果是，在成年骨基因生成剂中，NF1缺乏NF1的小鼠失去肌肉质量。这一发现以及其他体外和体内结果使我们挑战了肌肉内在缺陷的当前观点，并解决了骨源性的假设 NF1-NULL骨基因生成剂的因子有助于儿童观察到的肌肉无力使用NF1，也可以通过清除NF1-NULL OSTEOPENITOR的清除来缓解 Senolotics。总体而言，这项工作有可能改善NF1的临床管理假性关节炎具有一种策略，该策略将在物理上清除有缺陷的NF1无骨源性剂并营救其对造成骨修复的其他细胞的抑制作用，从而恢复稳健的骨再生。从机械上讲，这项研究可能支持NF1-NULL中的感应骨基因生成剂作为防止RAS诱导的突变损伤扩散的机制并以有害旁观者的影响对潜在的恶性转变排除骨修复和肌肉功能。