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Identifying the role of dynamic ECM-derived forces in zebrafish semicircular canal morphogenesis

识别动态 ECM 衍生力在斑马鱼半规管形态发生中的作用

基本信息

批准号：
10547914
负责人：
Akankshi Munjal
金额：
$ 24.9万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10547914
关键词：
Ablation Acceleration Address Alagille Syndrome Atlases Award Biological Models Biophysics Biosensor CHARGE syndrome CRISPR/Cas technology Cells Cellular biology Collaborations Complex Congenital Abnormality Data Set Deposition Development Developmental Biology Disease Ear Diseases Embryo Epithelial Equilibrium Etiology Event Extracellular Matrix Feedback Fingers Generations Genes Genetic Genetic Transcription Glycosaminoglycans Goals Grant Growth HAS3 gene Head Heparan Sulfate Proteoglycan Heparitin Sulfate Hyaluronan Hydrogels Image Image Analysis Interdisciplinary Study Jaw Laboratories Labyrinth Lasers Liquid substance Literature Maps Mechanics Mediating Mentors Mentorship Microfluidics Modeling Molecular Morphogenesis Organ Otic Vesicle Pathway interactions Pattern Phase Physics Polymers Postdoctoral Fellow Process Production Property Proteoglycan Publications Publishing Quantitative Microscopy Regenerative Medicine Regulation Reporter Research Resolution Role Semicircular canal structure Sequence Analysis Shapes Signal Transduction Simple Epithelium Specific qualifier value Swelling Syndrome Technology Testing Theoretical model Tissues Training Transgenic Organisms Translational Research Velocimetries Vertebrates Water Work Writing Xenopus Zebrafish automated image analysis base biophysical model biophysical properties biophysical tools career career development experience fundamental research gene synthesis high resolution imaging imaging genetics improved in vivo inner ear diseases insight mechanical force mechanical properties meetings morphogens mutant next generation novel particle pressure programs quantitative imaging response single cell sequencing single-cell RNA sequencing skills student mentoring tool transcription factor transcriptome versican zebrafish development

项目摘要

PROJECT SUMMARY The form of an organ defines its function. How simple epithelial tissues give rise to the complex forms of mature organs is a fundamental question in developmental biology with important implications in disease and regenerative medicine. A beautiful example is the remodeling of a simple embryonic epithelium to form the three semicircular canals (SCC) of the inner ear. Their intricate form is required for sensing balance and acceleration and is conserved across all jawed vertebrates. SCCs can develop abnormally in congenital syndromes such as LAMM, CHARGE and Alagille syndrome, for unknown reasons. The mechanisms underlying healthy development are poorly understood. My preliminary findings indicate that local synthesis of a hyaluronan-rich extracellular matrix (ECM) is important in SCC development. In the proposed research, I will determine how this ECM helps generate mechanical forces in SCC morphogenesis in zebrafish (Aim1). I will use next-generation single-cell sequencing to identify genes involved in the patterning of an active ECM (Aim2) and to identify and characterize the role of other ECM components involved in SCC development (Aim3). The novel molecular- mechanical principles revealed from this study will be widely applicable to other morphogenetic events involving an active ECM and topological epithelial remodeling. Moreover, as these processes are disrupted in many congenital diseases and ear disorders, my findings will improve our understanding of these diseases. The proposed research draws on 1) my training in quantitative cell biology in a development context, 2) the new skills acquired in my post-doctoral research, including zebrafish research and imaging of the developing organ at single-cell resolution, and 3) my K99 training plan to implement automated image analysis, in vivo biophysical measurements, modeling, and single-cell sequencing and analysis. To fulfil my aims, I will receive mentorship from Drs. Sean Megason, Tim Mitchison, L. Mahadevan and Allon Klein, whose combined expertise in zebrafish development, gene-editing, biophysics, quantitative imaging, modeling and single-cell RNA sequencing will give me the training I need to commence my independent research program. To facilitate my career development during the mentored K99 phase, I will take relevant courses and maintain collaborations for both fundamental and translational research, present my work at meetings, publish my research, write grants, and gain further experience in management and mentoring students to formulate my own mentoring style. I will greatly benefit from the experience, track record and regular feedback from my co-mentors to start my own laboratory. My long-term career goal is to head an inter-disciplinary research program to investigate the mechanical and molecular basis of morphogenesis and to use the insights I develop to advance translational research. I’ve made significant progress towards this goal in the form of research experience, successful collaborations and publications. The K99 award will give me access to the additional training and expertise I need to successfully transition to independence.

项目总结