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Clonal dynamics of the blood stem cell niche

血液干细胞生态位的克隆动力学

基本信息

批准号：
10569876
负责人：
Chloe Sophie Baron
金额：
$ 9.15万
依托单位：
BOSTON CHILDREN'S HOSPITAL
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：
2023-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10569876
关键词：
APLN gene Adult Advisory Committees Affect Algorithms Automobile Driving Award Bar Codes Biochemical Biological Assay Blood Blood Cells Blood Vessels Bone Marrow CRISPR/Cas technology Cell Maintenance Cell Proliferation Cells Clonality Clone Cells Color Computer Analysis Computing Methodologies Confocal Microscopy DNA Data Data Set Disease Disease Progression Disease model Dysmyelopoietic Syndromes Embryonic Development Endothelial Cells Endothelium Equilibrium Feedback Fibroblasts Flow Cytometry Gene Expression Profile Genetic Genetic Transcription Goals Hematological Disease Hematopoiesis Hematopoietic Hematopoietic stem cells Heterogeneity Hormone secretion Human In Vitro Journals Kidney Knowledge Laboratories Ligands Marrow Mediating Mentorship Methods Microscopic Modeling Molecular Mus Mutagenesis Organism Output Pathogenesis Pathway interactions Play Prize Proliferating Proto-Oncogenes Recovery Reporter Research Research Personnel Role Science Signal Pathway Signal Transduction Stromal Cells Technical Expertise Technology Testing Transgenic Organisms Transplantation Vascular Permeabilities Vascular remodeling Visualization Work Zebrafish adrenomedullin angiogenesis c-myc Genes cancer cell candidate identification career career development cell type computational basis confocal imaging hematopoietic stem cell niche improved in silico in vivo in vivo evaluation mosaic mouse model multidisciplinary multiple omics new therapeutic target next generation sequencing novel overexpression prevent progenitor programs promoter receptor reflectance confocal microscopy research and development response single cell mRNA sequencing stem stem cell biology symposium tool transcriptome transcriptomics

项目摘要

PROJECT SUMMARY The mechanisms by which the hematopoietic stem and progenitor (HSPC) niche is affected by clonal hematological disorders such as myelodysplastic syndrome (MDS) remain poorly understood. Furthermore, the heterogeneity and clonal response of endothelial and stromal cells (the main components of the HSPC niche) in MDS in vivo remain unexplored. To tackle these aspects, I developed a new zebrafish model of MDS by driving the protooncogene CMYC overexpression specifically in blood cells. Additionally, I crossed a genetic lineage tracing zebrafish line called GESTALT to a double transgenic zebrafish line carrying two fluorescent reporters allowing to purify specifically niche endothelial and stromal cells. This way, I created a new GESTALT line that permits CRISPR-CAS9 based barcoding during zebrafish embryonic development, purification of adult marrow niche cells and recovery of niche DNA barcodes by sequencing. Combining these novel tools, I induced MDS in barcoded zebrafish and read out the clonality and the transcriptome of endothelial and stromal cells. I discovered that clones of stromal cells selectively expand, and endothelial cells are transcriptionally remodeled in MDS. Given these data, I hypothesize that MDS remodels the clonality and transcriptional profile of the HSPC niche and that mechanisms involved in HSPC-niche interactions promote disease progression. Under the mentorship of Dr. Leonard Zon, I will investigate the mechanisms by which MDS remodels the niche using a combination of in silico computational approaches, genetic (GESTALT) and color based (Zebrabow) lineage tracing, confocal microscopy and in vivo mosaic mutagenesis. Once I establish my laboratory, I will build a multidisciplinary team to deepen my computational analyses and broaden my in vivo genetic and biochemical perturbations of the clonal mechanisms of niche involvement in MDS. My overarching goal is to identify novel targetable mechanisms specific to the HSPC niche that would prevent and/or halt MDS progression. This K99/R00 award will enable me to develop new technical skills, participate in courses that will improve my ability to manage a laboratory, and attend conferences that will broaden my network and my knowledge of hematological disease modeling, Zebrabow lineage tracing paired with confocal microscopy and zebrafish mutagenesis. The scientific advisory committee I have put together includes experts in the fields of hematopoiesis, lineage tracing, and stem cell biology and, along with Dr. Zon, will give me feedback on my research and career progress. These proposed research and career development activities will pave the way for me to become an independent investigator discovering and studying new mechanisms responsible for hematopoietic disorders progression mediated by the blood stem cell niche.

项目总结