Myogenic Mechanisms of Craniofacial Skeletal Muscle Regeneration

颅面骨骼肌再生的生肌机制

• 批准号: 10631961
• 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/10631961
• 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; Implant; 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; Morbidity - disease rate; 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; 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 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 此申请表是为Lauren博士颁发的临床科学家研究职业发展指导奖(K08) 卡茨。她目前正在进行头面部骨骼肌的研究，并观察到这块肌肉 与四肢和躯干的肌肉相比，TYPE有一个独特的再生程序。这款K08将增强Dr. Katz的能力1)成为头面部肌肉干细胞和再生方面的专家，2)进行基础 在一个很少被研究的组织中进行最高水平的科学研究，3)获得干细胞方面的尖端技能 包括单细胞RNA测序(scRNA-seq)和体外细胞移植在内的技术，4)在 提案开发、文稿准备和数据演示，以及5)开发高质量的 独立研究计划，将允许与来自 跨学科。为了实现这些目标，卡茨博士制定了一项明确而有重点的培训计划，并 确定了上述学科的专家。她的多学科指导团队 成员：James White博士(基础科学家，骨骼肌再生和干细胞)，William Maixner (临床医生-科学家，口腔和颅面研究)，Shannon Wallet(基础科学家，口腔和颅面 研究)、伊丽莎白·巴顿(基础科学家，骨骼肌再生)、凯文·伯德(临床医生-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(基础科学家，骨骼肌研究)和Simon Gregory(基础科学家，scRNA-seq)。 某些疾病患者存在重建功能性颅面肌的临床需要。 (肌肉营养不良、半面部矮小)、面部创伤和肿瘤切除。缺乏一种 对头面部肌肉及其干细胞种群的全面调查导致了一个很差的 了解这种组织在面对疾病或创伤时的再生能力。我们目前的情况 骨骼肌及其干细胞群的知识来自四肢肌肉；然而，它是 已知在胚胎起源上四肢肌肉和四肢肌肉之间存在明显的差异 头面部。因此，本研究的目的是利用损伤模型来阐明体内的损伤。 头面部骨骼肌再生能力及对分离的头面部进行深层表型鉴定 卫星细胞识别特定的头面部肌肉再生的分子靶点。再生能力 将使用肌肉再生的体内模型和体外细胞功能分析进行评估(目标1)。 将利用scrna-seq和体外干细胞移植来鉴定头面部肌肉特异性。 将使用慢病毒载体和慢病毒载体研究肌肉发生的调节因子(AIM 2)和确定的靶点 淘汰赛模型(目标3)。总之，K08的培训和指导将使Katz博士能够过渡到 自主研究，成为头面部肌肉再生医学领域的领先者 和转化性治疗。