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Wnt signaling in hematopoietic development

造血发育中的 Wnt 信号传导

基本信息

批准号：
10688191
负责人：
David Traver
金额：
$ 72.73万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10688191
关键词：
Anemia Area Autoimmunity Behavior Binding Biochemical Biochemistry Biological Biological Models Biology Blood Blood Cells Bone Marrow Bone Marrow Transplantation Cell Differentiation process Cell Lineage Cell Therapy Cells Clinic Clinical Cues Derivation procedure Development Developmental Biology Disease Embryo Engineering Epidermal Growth Factor Receptor Event FZD9 gene Gene Expression Profile Genetic Goals Hematological Disease Hematopoietic Hematopoietic Stem Cell Transplantation Hematopoietic System Hematopoietic stem cells Human Immune In Vitro Lateral Mesoderm Learning Life Maps Mediating Medicine Methods Molecular Molecular Target Monitor Motivation Mus Outcome Pathway interactions Patients Population Principal Investigator Property Protocols documentation Reporting Research Role Series Signal Transduction Somites Source Specificity Stem Cell Development Therapeutic Tissue Engineering Translating Transplantation Vertebrates WNT Signaling Pathway WNT9A gene Zebrafish cell regeneration differentiation protocol directed differentiation early embryonic stage effective therapy experimental study extracellular falls hematopoietic stem cell emergence hematopoietic stem cell expansion hematopoietic stem cell fate hemogenic endothelium human pluripotent stem cell human stem cells improved in vivo induced pluripotent stem cell insight interest leukemia novel pluripotency receptor reconstitution regenerative therapy single cell sequencing skills stem cell biology stem cell proliferation tool transcriptome transplantation therapy vertebrate embryos

项目摘要

Project Summary/Abstract: Hematopoietic stem cells (HSCs) give rise to all terminally differentiated cells in the blood. The ability of HSCs to reconstitute these blood cell lineages for life underlies the efficacy of bone marrow transplantation therapy for treatment of various blood disorders, including leukemias, anemia, and autoimmunity. Although this is an established and effective treatment, two-thirds of patients in need of a transplant lack a matched donor. Therefore, alternative sources of therapeutic HSCs would be a boon to the field. Human pluripotent stem cells (hPSCs) represent a potential source for cell-based therapies, including the derivation of patient-specific transplantable HSCs, which would additionally circumvent immune rejection and alloreactivity, both major issues in the clinic. The proposed collaborative research leverages the expertise of two Principal Investigators with complementary research interests and skills in stem cell biology, zebrafish genetics and development, murine HSC biology, hematopoietic development, and Wnt biology and biochemistry. Using zebrafish and hPSCs as model systems, they seek to identify and characterize the molecular cues that direct hematopoietic development during early embryonic stages, with an emphasis on the role of Wnt signaling. The proposed studies will build on their finding that a signaling axis regulated by Wnt9a/Frizzled9/EGFR is specifically required for HSC emergence and expansion across vertebrate phyla. This proposal will leverage lineage tracing methods in zebrafish and in vitro differentiation protocols of hPSCs combined with single-cell sequencing approaches to determine the molecular mechanisms of this requirement, and to provide a new level of understanding of how posterior lateral mesoderm is instructed to generate HSCs. The long-term goal of these studies is to gain a better understanding of how HSCs develop in the embryo in order to translate this information to hPSCs. Successful completion of this research will have a profound impact on HSC derivation and expansion, and thereby will be instrumental in overcoming current obstacles to the effective treatment of diseases requiring bone marrow transplant therapy.

项目总结/文摘:

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

WNT9A Is a Conserved Regulator of Hematopoietic Stem and Progenitor Cell Development.

WNT9A 是造血干细胞和祖细胞发育的保守调节因子。

DOI：
10.3390/genes9020066
发表时间：
2018
期刊：
Genes
影响因子：
3.5
作者：
Richter,Jenna;Stanley,EdouardG;Ng,ElizabethS;Elefanty,AndrewG;Traver,David;Willert,Karl
通讯作者：
Willert,Karl

Mechanisms of Wnt signaling and control.

DOI：
10.1002/wsbm.1422
发表时间：
2018-09
期刊：
Wiley interdisciplinary reviews. Systems biology and medicine
影响因子：
0
作者：
Grainger S;Willert K
通讯作者：
Willert K

Wnt9a Is Required for the Aortic Amplification of Nascent Hematopoietic Stem Cells.

DOI：
10.1016/j.celrep.2016.10.027
发表时间：
2016-11-01
期刊：
Cell reports
影响因子：
8.8
作者：
Grainger S;Richter J;Palazón RE;Pouget C;Lonquich B;Wirth S;Grassme KS;Herzog W;Swift MR;Weinstein BM;Traver D;Willert K
通讯作者：
Willert K

Wnt Signaling in Hematological Malignancies.