Calcium Signaling in Hematopoiesis

造血过程中的钙信号传导

• 批准号: 10379245
• 负责人: Sarah Chase Rothschild
• 金额: $ 7.76万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 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/10379245
• 关键词: Aorta; Apoptosis; Blood; Blood Cells; Bone Marrow Transplantation; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium; Calcium Signaling; Cell Lineage; Cells; Complex; Dorsal; Embryo; Endothelial Cells; Epigenetic Process; Genes; Genetic; Genetic Transcription; Goals; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Specification; Hematopoietic stem cells; Histone H3; Immune; Immune system; Individual; Life; Lysine; Malignant - descriptor; Methylation; Modeling; Molecular; Natural regeneration; Non-Malignant; Pathway interactions; Pattern; Pharmacology; Polycomb; Population; Proliferating; Rag1 Mouse; Role; Signal Pathway; Signal Transduction; Specific qualifier value; Supporting Cell; Techniques; Testing; Therapeutic; To specify; Zebrafish; calmodulin-dependent protein kinase II; cell type; directed differentiation; hemogenic endothelium; histone methyltransferase; improved; induced pluripotent stem cell; inhibitor; insight; knock-down; loss of function; notch protein; novel; self-renewal; transplantation therapy

Project Summary Current understanding of the molecular mechanisms underlying hematopoietic stem cell specification (HSCs) to generate induced pluripotent stem cells (iPS cells) is still limited. In this proposal, we seek to understand the role of calcium signaling, acting through CaMKII, in HSC specification in zebrafish embryos. Suppression of one of the seven transcriptionally active CaMKII genes, camk2g1, leads to increased expression of ezh2, the functional enzymatic component of the polycomb repressive complex 2 (PRC2), inhibiting HSC specification. We first seek to characterize the role of camk2g1 in HSC specification through use of genetic knockdown techniques and pharmacological inhibitors. We then seek to determine how increased expression of ezh2 in camk2g1 deficient embryos alters downstream signaling important for HSC specification. Preliminary results suggest increased ezh2 expression inhibits downstream expression of target genes (tgfbr2 and jag1a) resulting in apoptosis of HSCs in the ventral wall of the dorsal aorta. The results from this proposal will provide novel insight into the calcium-dependent signaling pathways necessary to generate all lineages of HSCs from iPS cells.

项目摘要 目前对造血干细胞规范(HSCs)的分子机制的了解 诱导多能干细胞(iPS细胞)的产生仍然有限。在这项提案中，我们试图了解 在斑马鱼胚胎的HSC规范中，钙信号通过CaMKII起作用。抑制其中一项 七个转录活性的CaMKII基因camk2g1导致EZH2表达增加，EZH2是功能 多梳抑制复合体2(PRC2)的酶成分，抑制HSC规范。我们首先寻求 通过使用基因敲除技术和基因敲除技术来表征Camk2g1在HSC指定中的作用 药理抑制剂。然后，我们试图确定在camk2g1缺陷中EZH2的表达增加是如何 胚胎改变下游信号，这对HSC的特性很重要。初步结果显示， EZH2的表达抑制靶基因(TGFBR2和jag1a)的下游表达，导致细胞凋亡 位于腹主动脉腹壁的HSCs。这项提案的结果将为我们提供对 从iPS细胞产生所有HSCs所必需的钙依赖的信号通路。