Fbxw7 as a target to promote muscle stem cell expansion

Fbxw7作为促进肌肉干细胞扩增的靶点

• 批准号: 9896756
• 负责人: Alessandra Sacco
• 金额: $ 21.45万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9896756
• 关键词: Ablation; Adult; Aging; Animal Model; Cell Compartmentation; Cell division; Cells; Chronic; Clinical; Disease; Disease model; FBXW7 gene; Gene Deletion; Genetic; Goals; Human; Immunodeficient Mouse; Impairment; In Vitro; Injury; Maintenance; Maps; Mediating; Molecular; Mus; Muscle function; Muscle satellite cell; Muscular Atrophy; Natural regeneration; Patients; Phenotype; Population; Process; Proliferating; Proteins; Proteomics; Regenerative Medicine; Research; Role; Skeletal Muscle; Source; Stress; Testing; Therapeutic; Time; Tissues; Transplantation; Ubiquitination; Validation; Wasting Syndrome; Work; adult stem cell; cell behavior; in vitro Model; in vivo; inhibitor/antagonist; muscle regeneration; novel; novel strategies; progenitor; protein degradation; protein protein interaction; repaired; self-renewal; skeletal muscle growth; stem cell fate; stem cells; therapy development; tissue regeneration; tissue repair; tool; ubiquitin-protein ligase

SUMMARY The goal of this proposal is to define novel approaches to promote muscle stem cells (MuSC) expansion. MuSC are the major source of skeletal muscle growth and regeneration. This cell population is capable of self-renewal, i.e. generating large number of progenitors to repair damaged tissue and at the same time more copies of themselves upon cell division to maintain the stem cell pool. MuSC exist in healthy adult tissues in a quiescent state, and upon stress or injury they are activated to proliferate and repair the damaged tissue. While this process is efficient in healthy conditions, in several diseased states and during aging the function of MuSC is impaired and this significantly contribute to impaired tissue maintenance and function. However, their clinical utility as therapeutic tools and targets is currently hindered by our limited understanding of the molecular networks regulating their function. Thus, there is a major need to fill this gap and define novel approaches that can promote MuSC expansion and tissue repair, as these would find applications for disease modeling in vitro as well as for promoting MuSC-mediated tissue regeneration in chronic conditions. Our preliminary results provide evidence that the E3 ubiquitin ligase Fbxw7, which regulates multiple adult stem cell compartments, promotes MuSC commitment and differentiation, and its genetic ablation leads to robust MuSC expansion in vivo. The focus of the proposed studies is to dynamically map Fbxw7 protein targets during MuSC fate transitions, and to evaluate its transient inhibition as a novel approach to promote MuSC expansion. Our research will take advantage of (1) the inducible Pax7-CreER;Fbxw7f/f novel animal model, (2) an optimized global proteomics approach for MuSC profiling, (3) the use of Fbxw7 inhibitors for its transient manipulation, and (4) Human MuSC isolated from patients, to validate conservation across species. Together, this exploratory study will provide an initial understanding of how Fbxw7 impacts MuSC cell fate decisions and identify novel tools that can be utilized for regenerative medicine approaches to enhance MuSC expansion and tissue repair in diseased conditions.

概括 该提案的目标是定义促进肌肉干细胞（MuSC）扩增的新方法。穆斯卡 是骨骼肌生长和再生的主要来源。该细胞群具有自我更新能力， 即产生大量的祖细胞来修复受损的组织，同时产生更多的祖细胞副本 细胞分裂时自身维持干细胞库。 MuSC 以静止状态存在于健康成人组织中 状态下，当受到压力或受伤时，它们会被激活以增殖并修复受损的组织。虽然这个过程 在健康状况下有效，在多种疾病状态下和衰老过程中 MuSC 的功能会受损 这会严重损害组织的维护和功能。然而，它们的临床实用性 目前，我们对分子网络的了解有限，阻碍了治疗工具和靶点的发展 调节它们的功能。因此，迫切需要填补这一空白并定义可以促进的新方法 MuSC 扩增和组织修复，因为这些将在体外疾病模型以及 促进慢性疾病中 MuSC 介导的组织再生。我们的初步结果提供了证据 E3 泛素连接酶 Fbxw7 调节多个成体干细胞区室，促进 MuSC 定型和分化，其基因消融导致 MuSC 在体内强劲扩张。重点是 拟议的研究是在 MuSC 命运转变期间动态映射 Fbxw7 蛋白靶标，并 评估其瞬时抑制作为促进 MuSC 扩增的新方法。我们的研究将采取 (1) 诱导型 Pax7-CreER;Fbxw7f/f 新型动物模型的优点，(2) 优化的全局蛋白质组学 MuSC 分析方法，(3) 使用 Fbxw7 抑制剂进行瞬时操作，以及 (4) 人类 MuSC 从患者身上分离出来，以验证跨物种的保护。总之，这项探索性研究将提供 初步了解 Fbxw7 如何影响 MuSC 细胞命运决定并确定可以利用的新工具 用于增强患病条件下 MuSC 扩张和组织修复的再生医学方法。