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MEKK3 signaling in hemogenic endothelium

造血内皮细胞中的 MEKK3 信号传导

基本信息

批准号：
10198023
负责人：
MARK L KAHN
金额：
$ 76.08万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10198023
关键词：
Anemia Aorta Arteries Biological Assay Blood Cells Blood flow Brain Cardiac Cell Maturation Cells Clinical Cues Data Development Dorsal Embryo Embryonic Heart Endothelial Cells Endothelium Erythro Event Failure Gene Expression Genetic Transcription Globin Hematopoiesis Hematopoietic Hematopoietic Stem Cell Transplantation Hematopoietic stem cells In Vitro Inflammatory Life Liquid substance MAP Kinase Gene Mammals Measures Mechanical Stimulation Mediating Multipotent Stem Cells Myelogenous Pathway interactions Population Process Regulation Role Signal Pathway Signal Transduction Site Stimulus System Testing Therapeutic Vascular Endothelial Cell Vertebrates Yolk Sac Zebrafish combinatorial cytokine defined contribution endothelial-hematopoietic transition extracellular fetal hemodynamics hemogenic endothelium in vivo insight mouse development mouse model postnatal progenitor response single-cell RNA sequencing stem cells transcription factor

项目摘要

Project Summary Embryonic definitive hematopoiesis is initiated by endothelial-hematopoietic transition (EHT) in which endothelial cells alter fate to become hematopoietic progenitors and stem cells. In mammals there are two major sites of EHT, the yolk sac vasculature and the major arteries of the embryo (dorsal aorta, vitelline, umbilical). Although the process of EHT is highly conserved and required for definitive hematopoiesis in all vertebrates, the signals that control the conversion of vascular endothelial cells to hemogenic endothelial cells are poorly understood. Recent studies have implicated hemodynamic shear forces and inflammatory cytokines in promoting EHT, but how these diverse signals stimulate the formation of hemogenic endothelium remains unknown. We have previously demonstrated that the MEKK3 MAPK pathway mediates endothelial cell responses to both inflammatory cytokines and hemodynamic shear forces, in large part by increasing expression of the KLF2 and KLF4 transcription factors. Our preliminary studies demonstrate that endothelial loss of MEKK3 or KLF2+KLF4 results in lethal fetal anemia and failure of EHT in both the yolk sac and embryo. This proposal will test the hypothesis that MEKK3-KLF2/4 signaling integrates endothelial cell stimulation by cytokines and fluid forces to trigger EHT and the onset of definitive hematopoiesis. These studies are expected to yield new insight into the signals that initiate EHT, findings that may be used to generate new hematopoietic stem and progenitor cells for therapeutic purposes later in life.

项目总结