Role of STAT3 in muscle stem cell activation

STAT3 在肌肉干细胞激活中的作用

• 批准号: 8910636
• 负责人: Alessandra Sacco
• 金额: $ 42.11万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-11 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8910636
• 关键词: Ablation; Acute; Adult; Animals; Biological Assay; Biopsy; Cell Nucleus; Cell Proliferation; Cell physiology; Cell surface; Chronic; Cues; DNA Binding; Degenerative Disorder; Development; Equilibrium; Event; Foundations; Gene Deletion; Gene Expression; Gene Expression Profiling; Gene Targeting; Genetic; Genetic Transcription; Goals; Health; Homeostasis; Human; Immunodeficient Mouse; In Situ; Inflammatory; Injury; Interleukin-6; Janus kinase; Knowledge; Luciferases; Maintenance; Mediating; Microscopy; Molecular; Molecular Analysis; Monitor; Muscle; Muscle function; Muscle satellite cell; MyoD Protein; Myogenic Regulatory Factors; Pathway interactions; Patients; Phosphorylation; Play; Process; Proliferating; Proteins; Regenerative Medicine; Reporter; Research; Role; STAT3 gene; Signal Pathway; Signal Transduction; Skeletal Muscle; Source; Stress; System; Testing; Therapeutic; Time; Tissues; Transcriptional Activation; Wasting Syndrome; Work; Xenograft procedure; chromatin immunoprecipitation; cytokine; improved; in vivo; injury and repair; loss of function; meetings; muscle regeneration; mutant; novel; progenitor; regenerative; repaired; satellite cell; self-renewal; therapeutic development; tissue regeneration; tissue repair; tool

DESCRIPTION (provided by applicant): Adult muscle stem cells (MuSC), also known as satellite cells, are the main source skeletal muscle regeneration. MuSC exist in healthy adult tissues in a quiescent state, and upon stress or injury they are activated to proliferate and generate large numbers of progenitors to repair the damaged tissue. Although the balance between quiescence and activation is a critical switch in MuSC function, the molecular mechanisms regulating this transition are still largely unknown. An improved understanding of the networks regulating MuSC function would facilitate their use in regenerative medicine for the development of therapeutic approaches for muscle wasting diseases. Our preliminary findings indicate that STAT3 regulates MuSC proliferation as well as plays a direct role in the transcriptional activation of the bHLH myogenic regulatory factor MyoD, a key event as MuSC exit the quiescent state. Upon cytokine stimulation, STAT3 is phosphorylated by JAK kinases, translocates to the nucleus and binds DNA to activate the transcription of target genes. The focus of this proposal is to investigate the role of the STAT3 in MuSC self-renewal, activation and myogenic commitment and to identify its relevant downstream targets. Our research will take advantage of the following tools: (1) Loss of function studies in conjunction with time-lapse microscopy, to monitor MuSC activation in situ, (2) Chromatin ImmunoPrecipitation (ChIP), ChIPseq and microarray gene expression profiling, in order to identify novel STAT3 downstream targets in MuSC, (3) Conditional genetic ablation of STAT3 in MuSC, in order to evaluate its role in MuSC self-renewal and maintenance in vivo in the intact animal, and (4) Human MuSC isolated from patients, to determine whether the critical role of STAT3 in MuSC function is conserved in between the two species. Together, these studies would identify a direct functional interaction between STAT3 and MyoD, and further extend our knowledge of the STAT3 regulatory network in MuSC activation. Finally, these findings would aid in the development of strategies aimed at promoting muscle stem cell-mediated tissue regeneration to ameliorate muscle-wasting diseases.

描述（申请人提供）：成体肌肉干细胞（MuSC），又称卫星细胞，是骨骼肌再生的主要来源。 MuSC 以静止状态存在于健康成人组织中，在受到压力或损伤时，它们被激活增殖并产生大量祖细胞来修复受损组织。尽管静止和激活之间的平衡是 MuSC 功能的关键转换，但调节这种转变的分子机制仍然很大程度上未知。对调节 MuSC 功能的网络的进一步了解将有助于其在再生医学中的应用，以开发肌肉萎缩疾病的治疗方法。我们的初步研究结果表明，STAT3 调节 MuSC 增殖，并在 bHLH 生肌调节因子 MyoD 的转录激活中发挥直接作用，这是 MuSC 退出静止状态的关键事件。在细胞因子刺激下，STAT3 被 JAK 激酶磷酸化，转位到细胞核并结合 DNA 以激活靶基因的转录。该提案的重点是研究 STAT3 在 MuSC 自我更新、激活和肌源性承诺中的作用，并确定其相关的下游靶点。我们的研究将利用以下工具：(1) 与延时显微镜相结合的功能丧失研究，以监测 MuSC 原位激活，(2) 染色质免疫沉淀 (ChIP)、ChIPseq 和微阵列基因表达谱分析，以确定 MuSC 中新的 STAT3 下游靶标，(3) MuSC 中 STAT3 的条件性基因消除，以评估其在 MuSC 中的作用 (4) 从患者身上分离出人类 MuSC，以确定 STAT3 在 MuSC 功能中的关键作用在两个物种之间是否保守。总之，这些研究将确定 STAT3 和 MyoD 之间的直接功能相互作用，并进一步扩展我们对 MuSC 激活中 STAT3 调控网络的了解。最后，这些发现将有助于制定旨在促进肌肉干细胞介导的组织再生以改善肌肉萎缩疾病的策略。