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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

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.

项目摘要本建议书描述了一个为期五年的指导培训经验，旨在为申请人的职业生涯做好准备在基础和转化科学研究中。申请人持有医学博士学位。和博士学位，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一名医生- 研究骨骼发育不良分子遗传基础的科学家。职业发展计划包括指导，正式课程，实验室会议，研讨会，全国会议，并与咨询会议以马克思该计划旨在拓宽申请人的研究技能，包括课程作业和在模式生物、糖蛋白组学、显微成像和生物统计学方面的实验学习。此外，本发明还提供了一种方法，拟议的计划将提供领导能力、指导、实验室管理、科学写作和编辑，补助金写作，以及研究的伦理影响。分子和人类遗传学系贝勒医学院在培养非常成功的内科医生科学家方面有着悠久的历史。的我的导师Brendan Lee博士是骨骼发育不良领域的领先专家，为超过9名K和VA职业发展获奖者提供指导，所有这些人都进入了独立实验室- 研究为基础的职业。选择咨询委员会是为了补充导师的专业知识，为申请人提供重要的研究和职业指导。拟议的研究将调查骨中COPB 2单倍不足的功能、细胞和生物化学后果。功能丧失 COPB 2是COPI外被体复合物的一个亚单位，在发育不良的儿童中发现了COPB 2的变异。延迟和骨脆性。COPI的功能是在内质网和高尔基体之间以及高尔基体内部进行运输蓄水池囊泡运输缺陷，包括COPI功能障碍，与骨骼发育不良有关。初步数据表明，Copb 2 +/-小鼠表现出低骨量表型，而copb 2缺失的斑马鱼表现出低骨量表型。胚胎表现出前胶原的异常分泌。申请人提出COPB 2缺乏导致骨脆性通过引起延迟的胶原运输，高尔基体-ER功能障碍和改变的自噬，导致破坏成骨细胞分化。这项研究涉及分析骨骼表型， COPB 2缺陷小鼠模型，包括在特定阶段骨中选择性缺失Copb 2，成骨细胞分化（“条件性敲除”）。通过采用这种方法，申请人将确定在在骨骼发育期间的哪个时间点，COPB 2的缺乏变得至关重要。拟定研究还旨在检查COPB 2缺陷是否改变蛋白质糖基化，并导致ER-高尔基体功能障碍，这些变化是否适合治疗。这项研究将涉及COPB 2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，并利用先进的技术，和拟议的职业发展计划将准备这个申请人的职业生涯作为一个独立研究科学家。