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Ion signaling and cell state transitions for organ size control of regenerating zebrafish fins

离子信号和细胞状态转变用于控制再生斑马鱼鳍的器官大小

基本信息

批准号：
10402793
负责人：
Heather K Le Bleu
金额：
$ 4.52万
依托单位：
UNIVERSITY OF OREGON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10402793
关键词：
Adult Affect Amputation Animals Back Bone Diseases Calcineurin Calcium Cardiac Cell Lineage Cells Cellular biology Communication Data Data Set Development Developmental Biology Disease Distal Doctor of Philosophy Dominant-Negative Mutation Ectopic Expression Educational process of instructing Educational workshop Event Genes Genetic Epistasis Geometry Growth Health Homologous Gene Human Image Injury Ion Channel Ions Kinetics Laboratories Leadership Long QT Syndrome Mentors Mesenchymal Mesenchyme Modeling Molecular Natural regeneration Organ Organ Model Organ Size Pathway interactions Phenotype Population Potassium Channel Production Publishing Regenerative Medicine Regenerative capacity Reporter Research Resected Role Science Shapes Signal Transduction Site Skeleton Testing Time Tissues Training Training Activity Transgenic Organisms Transplantation Voltage-Gated Potassium Channel WNT Signaling Pathway Woman Zebrafish base bioelectricity blastema bone calcineurin phosphatase cell behavior experience experimental study human disease human tissue in vivo injured mutant novel strategies organ repair prevent regenerative regenerative biology repaired restoration skeletal small molecule therapeutic target transcription factor transcriptomics voltage

项目摘要

PROJECT SUMMARY This project provides the applicant with Ph.D. training intersecting cell, developmental and regenerative biology. Zebrafish regenerate resected fins, including their bony ray skeletons, back to the original size irrespective of injury extent. Yet, how fins “know” when to stop growing as the correct size is attained is poorly understood. The applicant’s laboratory recently proposed a new model for robust fin size restoration based on initial amount of a skeletal geometry-defined “niche” population and its progressive depletion by a cell state transition. Further, the group found dramatic fin overgrowth in the classic zebrafish mutant longfint2 is caused by cis-ectopic expression of the kcnh2a K+ channel. Kcnh2a in longfint2 results in niche cell perdurance and therefore excessive outgrowth during regeneration. The applicant’s transplant experiments show ectopic kcnh2a in the mesenchyme lineage that generates niche cells is sufficient for overgrowth. Yet, how kcnh2a disrupts orderly niche depletion is unknown. Published studies show inhibiting the Ca2+-dependent phosphatase calcineurin also causes striking fin overgrowth. The applicant’s new epistasis experiments suggest Kcnh2a functions upstream of calcineurin. Their new transgenic Ca2+ reporter identifies dynamic Ca2+ levels in niche/mesenchyme cells that preliminary transcriptomics indicate depend on specifically expressed Ca2+ channels. This leads to the central hypothesis that Ca2+ channel activity and dynamic Ca2+ levels activate calcineurin signaling to promote niche-to-mesenchymal cell state transitions and end fin regrowth. The applicant will pursue three specific aims: 1) Determine how Kcnh2a impacts intracellular Ca2+ dynamics during fin regeneration, 2) Identify Ca2+ channels influencing regenerated fin size, and 3) Determine if calcineurin promotes niche-to-mesenchymal cell state transitions to slow fin outgrowth. In parallel with thesis research, the applicant will pursue extensive scientific communication training and activities, mentoring and teaching experiences, professional development workshops and networking events, and a diversity-supporting leadership role in the Women in Graduate Science organization.

项目总结