ELUCIDATING THE ROLE OF COATOMER COMPLEX COPI IN SKELETAL DYSPLASIA

阐明 COATOMER 复合物 COPI 在骨骼发育不良中的作用

基本信息

批准号：
10591042
负责人：
Ronit Marom
金额：
$ 13.4万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10591042
关键词：
Acids Advisory Committees Affect American Autophagocytosis Basic Science Biochemical Biogenesis Biological Assay Biological Models Biometry Bone Development Carrier Proteins Cell Cycle Cell physiology Cells Certification Child Childhood Clinical Collagen Complement Complex Data Defect Deposition Development Development Plans Developmental Delay Disorders Diagnostic Disease Doctor of Medicine Doctor of Philosophy Electron Microscopy Embryo Enterobacteria phage P1 Cre recombinase Ethics Etiology Exhibits Extracellular Matrix Proteins Failure Fracture Functional disorder Future Genes Genetic Diseases Genomics Glycols Goals Golgi Apparatus Grant Heterozygote Histology Human Human Genetics Immunologic Deficiency Syndromes In Vitro Individual Intellectual functioning disability Kinetics Knockout Mice Laboratories Laboratory Research Leadership Learning Lectin Lipids Medical Genetics Medicine Mentors Mentorship Modeling Molecular Genetics Mus Organelles Osteoblasts Osteogenesis Imperfecta Osteopenia Osteoporosis Other Genetics Pathogenesis Pathogenicity Pathway interactions Patients Phenotype Physicians Polarization Microscopy Procollagen Protein Glycosylation Protein Secretion Proteomics Recurrence Research Research Design Role Scientist Skeletal Development Skeletal system Skeleton Sorting Stains Structure System Technology Testing Time Tissues Training Transgenic Organisms Translational Research Variant Vocational Guidance Work Writing Zebrafish body system bone bone fragility bone mass career career development college conditional knockout design diagnostic strategy diagnostic value endoplasmic reticulum stress experience experimental study glycoproteomics glycosylation in vivo insight live cell microscopy loss of function meetings microCT microscopic imaging model organism molecular phenotype mouse model multimodality osteoblast differentiation protein transport proteostasis rare mendelian disorder screening skeletal skeletal abnormality skeletal dysplasia skills symposium targeted treatment trafficking transcriptomics translational impact treatment strategy

Acids Advisory Committees Affect American Autophagocytosis Basic Science Biochemical Biogenesis Biological Assay Biological Models Biometry Bone Development Carrier Proteins Cell Cycle Cell physiology Cells Certification Child Childhood Clinical Collagen Complement Complex Data Defect Deposition Development Development Plans Developmental Delay Disorders Diagnostic Disease Doctor of Medicine Doctor of Philosophy Electron Microscopy Embryo Enterobacteria phage P1 Cre recombinase Ethics Etiology Exhibits Extracellular Matrix Proteins Failure Fracture Functional disorder Future Genes Genetic Diseases Genomics Glycols Goals Golgi Apparatus Grant Heterozygote Histology Human Human Genetics Immunologic Deficiency Syndromes In Vitro Individual Intellectual functioning disability Kinetics Knockout Mice Laboratories Laboratory Research Leadership Learning Lectin Lipids Medical Genetics Medicine Mentors Mentorship Modeling Molecular Genetics Mus Organelles Osteoblasts Osteogenesis Imperfecta Osteopenia Osteoporosis Other Genetics Pathogenesis Pathogenicity Pathway interactions Patients Phenotype Physicians Polarization Microscopy Procollagen Protein Glycosylation Protein Secretion Proteomics Recurrence Research Research Design Role Scientist Skeletal Development Skeletal system Skeleton Sorting Stains Structure System Technology Testing Time Tissues Training Transgenic Organisms Translational Research Variant Vocational Guidance Work Writing Zebrafish body system bone bone fragility bone mass career career development college conditional knockout design diagnostic strategy diagnostic value endoplasmic reticulum stress experience experimental study glycoproteomics glycosylation in vivo insight live cell microscopy loss of function meetings microCT microscopic imaging model organism molecular phenotype mouse model multimodality osteoblast differentiation protein transport proteostasis rare mendelian disorder screening skeletal skeletal abnormality skeletal dysplasia skills symposium targeted treatment trafficking transcriptomics translational impact treatment strategy

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项目摘要

PROJECT SUMMARY This proposal describes a five-year mentored training experience designed to prepare the applicant for a career in basic and translational science research. The applicant holds M.D. and Ph.D. degrees, and is certified by the American Board of Medical Genetics and Genomics. The applicant’s long-term goal is to become a physician- scientist studying the molecular genetic basis of skeletal dysplasias. The career development plan includes mentorship, formal coursework, lab meetings, seminars, national conferences, and meetings with the advisory committee. The plan is designed to broaden the applicant’s research skills, including coursework and experimental learning in model organisms, glycoproteomics, microscopy imaging, and biostatistics. In addition, the proposed plan will provide training in leadership, mentorship, laboratory management, scientific writing and editing, grant writing, and the ethical implications of research. The Department of Molecular and Human Genetics at Baylor College of Medicine has a long track record of training highly successful physician scientists. The mentor, Dr. Brendan Lee, is a leading expert in the field of skeletal dysplasia and has been the primary research mentor for over 9 K and VA career development awardees, all of whom have gone onto independent laboratory- research based careers. The advisory committee was selected to complement the mentor’s expertise and to provide important research and career guidance for the applicant. The proposed study will investigate the functional, cellular, and biochemical consequences of COPB2 haploinsufficiency in bone. Loss-of-function variants in COPB2, a subunit of the COPI coatomer complex, were identified in children with developmental delay and bone fragility. The COPI functions in trafficking between the ER and Golgi, and within the Golgi cisternae. Vesicular trafficking defects, including COPI dysfunction, have been implicated in skeletal dysplasia. Preliminary data demonstrated that Copb2+/- mice exhibit a low bone mass phenotype, and copb2-null zebrafish embryos show abnormal secretion of procollagen. The applicant proposes that COPB2 deficiency leads to bone fragility by causing delayed collagen trafficking, Golgi-ER dysfunction, and altered autophagy, resulting in disruption of osteoblast differentiation. The proposed study involves analysis of the skeletal phenotype in COPB2-deficient mouse models, including selective deletion of Copb2 in bone during specific stages of osteoblast cell differentiation (“conditional knock-out”). By taking this approach, the applicant will determine at which time point during skeletal development the deficiency of COPB2 becomes critical. The proposed study also aims to check if COPB2 deficiency alters protein glycosylation, and causes an ER-Golgi dysfunction, and whether these changes may be amenable to therapy. The study will involve the analysis of COPB2-deficient mouse models and cells. This application, which provides a broad research experience and utilizes advanced technologies, and the proposed career development plan will prepare this applicant for a career as an independent research scientist.

项目摘要该提案描述了五年的培训经验，旨在为申请人做准备职业在基础和翻译科学研究中。申请人拥有医学博士学位和博士学位学位，并由美国医学遗传学和基因组学委员会。申请人的长期目标是成为身体研究骨骼发育不良的分子遗传基础的科学家。职业发展计划包括精通训练，正式课程工作，实验室会议，半小伙，民族会议和与咨询会议委员会。该计划旨在扩大申请人的研究技能，包括课程和模型生物，糖蛋白质组学，显微镜成像和生物统计学中的实验学习。此外，拟议的计划将提供领导，指导，实验室管理，科学写作和的培训编辑，赠款写作以及研究的道德意义。分子和人类遗传学系在贝勒医学院，培训非常成功的物理科学家的悠久记录。这导师布伦丹·李（Brendan Lee）博士是骨骼发育不良领域的领先专家，一直是主要研究超过9 K和VA职业发展奖的导师，他们都参加了独立实验室 - 基于研究的职业。选择咨询委员会来完成心理专业知识和为适用的重要研究和职业指导。拟议的研究将调查 COPB2单倍不使骨中的功能性，细胞和生化后果。功能丧失 COPB2中的变体是COPI座椅络合物的一个亚基，在发育中的儿童中鉴定延迟和骨骼脆弱。 COPI在急诊室和高尔基体之间以及高尔基体之间的运输中起作用水库。在骨骼发育不良中隐含了包括COPI功能障碍在内的囊泡贩运缺陷，包括COPI功能障碍。初步数据表明COPB2 +/-小鼠表现出低骨质量表型，而COPB2-NULL斑马鱼胚胎表现出异常分泌procollagen。 COPB2缺乏导致骨骼的申请人提议通过引起延迟的胶原蛋白运输，高尔基-ER功能障碍和自噬改变，导致脆弱性，从而导致成骨细胞分化的破坏。拟议的研究涉及对骨骼表型的分析 COPB2缺乏鼠标模型，包括在特定阶段的骨骼中COPB2的选择性删除成骨细胞分化（“条件敲除”）。通过采用这种方法，申请人将确定骨骼发育期间的哪个时间点COPB2的缺乏变得至关重要。拟议的研究还旨在检查COPB2缺乏症是否改变了蛋白质糖基化，并引起er-Golgi功能障碍，并且这些变化是否可能适合治疗。该研究将涉及COPB2缺陷的分析小鼠模型和细胞。该应用程序提供了广泛的研究经验，并利用了高级技术和拟议的职业发展计划将为该申请人做好准备的职业独立研究科学家。