Myogenic Mechanisms of Craniofacial Skeletal Muscle Regeneration

颅面骨骼肌再生的生肌机制

• 批准号: 10442681
• 负责人: Lauren Katz McKay
• 金额: $ 17万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10442681
• 关键词: Affect; Appearance; Basic Science; Biological Assay; Biology; Birth; Breathing; Cell Separation; Cell Transplantation; Cell physiology; Cells; Cellular Assay; Clinical; Data; Data Analyses; Defect; Deglutition; Development; Discipline; Disease; Eating; Environment; Excision; Face; Facial asymmetry; Foundations; Gene Expression Profile; Genes; Genomics; Goals; Impairment; In Vitro; Individual; Injury; Investigation; K-Series Research Career Programs; Knock-out; Knowledge; Lentivirus Vector; Life; Limb structure; Literature; Malignant Neoplasms; Manuscripts; Masseter Muscle; Mastication; Mediating; Mentors; Mentorship; Methodology; Modality; Modeling; Molecular; Molecular Target; Muscle; Muscle Fibers; Muscle function; Muscle satellite cell; Muscular Dystrophies; Myopathy; Natural regeneration; Oral; Patients; Phenotype; Population; Preparation; Quality of life; Regenerative Medicine; Regenerative capacity; Regulation; Research; Role; Scientist; Skeletal Muscle; Stem cell transplant; Techniques; Technology; Testing; Therapeutic; Time; Tissue-Specific Gene Expression; Tissues; Training; Trauma; Viral; base; career; craniofacial; craniofacial disorder; differential expression; effective therapy; experimental study; genetic manipulation; in vivo; in vivo Model; molecular phenotype; multidisciplinary; muscle regeneration; myogenesis; negative affect; novel; novel strategies; oral biology; orofacial; programs; regeneration potential; regenerative; response to injury; restoration; satellite cell; single-cell RNA sequencing; skeletal; skills; stem; stem cell population; stem cell self renewal; stem cells; tissue regeneration; translational therapeutics; tumor

ABSTRACT This application is for a Mentored Clinical Scientist Research Career Development Award (K08) for Dr. Lauren Katz. She is currently conducting research on craniofacial skeletal muscle and has observed that this muscle type has a unique regenerative program compared to muscles of the limb and trunk. This K08 will enhance Dr. Katz's ability to 1) become an expert in craniofacial muscle stem cells and regeneration, 2) conduct basic science research at the highest level in a tissue rarely studied, 3) acquire cutting-edge skills in stem cell techniques including single-cell RNA sequencing (scRNA-seq) and ex vivo cell transplantation, 4) gain skills in proposal development, manuscript preparation, and data presentation, and 5) develop a high-quality independent research program that will allow for collaborative opportunities with scientists and clinicians from across disciplines. To achieve these goals, Dr. Katz has devised a clear and focused training plan and has identified individuals who are experts in the aforementioned disciplines. Her multidisciplinary mentoring team consists of: Drs. James White (basic scientist, skeletal muscle regeneration and stem cells), William Maixner (clinician-scientist, oral and craniofacial research), Shannon Wallet (basic scientist, oral and craniofacial research), Elisabeth Barton (basic scientist, skeletal muscle regeneration), Kevin Byrd (clinician-scientist, oral stem cells), Lyndon Cooper (clinician-scientist, oral stem cells), Eric Everett (basic scientist, oral biology), Jimena Giudice (basic scientist, skeletal muscle research), and Simon Gregory (basic scientist, scRNA-seq). There exists a clinical need to rebuild functional craniofacial muscle in patients suffering from certain diseases (muscular dystrophy, hemifacial microsomia), facial trauma, and tumor resections. The lack of a comprehensive investigation of the craniofacial musculature and its stem population has resulted in a poor understanding of the regenerative capacity of this tissue when faced with disease or trauma. Our current knowledge of skeletal muscles and their stem cell populations comes from the limb muscles; however, it is known that distinct differences in embryological origin exist between muscles of the limb and those of the craniofacial region. Therefore, the objectives of this study are to use injury models to elucidate the in vivo regenerative capacity of craniofacial skeletal muscle and to perform deep phenotyping on isolated craniofacial satellite cells to identify molecular targets specific to craniofacial muscle regeneration. Regenerative capacity will be assessed using in vivo models of muscle regeneration and in vitro cellular function assays (Aim 1). scRNA-seq and ex vivo stem cell transplantation will be utilized to identify craniofacial muscle-specific regulators of myogenesis (Aim 2) and identified targets will be investigated using lentiviral vectors and knockout models (Aim 3). Together, the K08 training and mentorship will enable Dr. Katz to transition into an independent research career and become a leader in the field of craniofacial muscle regenerative medicine and translational therapeutics.

摘要 此应用程序是指导临床科学家研究职业发展奖（K 08）博士劳伦 卡茨她目前正在进行颅面骨骼肌的研究，并观察到这种肌肉 与四肢和躯干的肌肉相比，类型有一个独特的再生程序。这款K 08将增强Dr. 卡茨的能力，1）成为专家在颅面肌肉干细胞和再生，2）进行基本的 在一个组织很少研究的最高水平的科学研究，3）获得干细胞的尖端技能 技术，包括单细胞RNA测序（scRNA-seq）和体外细胞移植，4）获得技能， 提案开发，手稿准备和数据演示，以及5）开发高质量的 独立的研究计划，将允许与科学家和临床医生合作的机会，从 跨学科。为了实现这些目标，Katz博士制定了一个明确而有针对性的培训计划， 确定了上述学科的专家。她的多学科指导团队 包括：James白色博士（基础科学家，骨骼肌再生和干细胞），William Maixner （临床科学家，口腔和颅面研究），香农钱包（基础科学家，口腔和颅面研究） 研究），伊丽莎白巴顿（基础科学家，骨骼肌再生），凯文伯德（临床科学家，口腔 干细胞），林登库珀（临床科学家，口腔干细胞），埃里克埃弗雷特（基础科学家，口腔生物学）， Jimena Giudice（骨骼肌研究基础科学家）和Simon Gregory（scRNA-seq基础科学家）。 临床上存在着对患有某些疾病的患者进行功能性颅面肌重建的需求 （肌肉营养不良、半面矮小）、面部创伤和肿瘤切除术。缺乏一个 对颅面肌肉系统及其干细胞群的全面调查导致了 了解这种组织在面对疾病或创伤时的再生能力。我们目前 骨骼肌及其干细胞群的知识来自肢体肌肉;然而， 已知在胚胎学起源上的明显差异存在于肢体的肌肉和肌肉之间。 颅面区因此，本研究的目的是使用损伤模型来阐明体内 颅面骨骼肌的再生能力，并对分离的颅面进行深层表型分析 卫星细胞，以确定特定的颅面肌肉再生的分子目标。再生能力 将使用肌肉再生的体内模型和体外细胞功能测定来评估（目的1）。 scRNA-seq和离体干细胞移植将用于鉴定颅面肌特异性 肌生成的调节因子（Aim 2）和鉴定的靶点将使用慢病毒载体进行研究， 淘汰模型（目标3）。总之，K 08培训和指导将使Katz博士能够过渡到一个 独立的研究事业，成为颅面肌再生医学领域的领导者 和转化疗法。