Hematopoietic Signaling Pathway Mechanism in a GATA Factor-Dependent Network

GATA 因子依赖性网络中的造血信号通路机制

• 批准号: 10672858
• 负责人: Kyle J Hewitt
• 金额: $ 11.51万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10672858
• 关键词: Acute Myelocytic Leukemia; Adult; Anemia; Centers of Research Excellence; Collaborations; Development; Dysmyelopoietic Syndromes; Elements; Enhancers; Foundations; Funding; Genes; Genetic Transcription; Goals; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; Immunologic Deficiency Syndromes; Malignant neoplasm of pancreas; Mentorship; Mission; Molecular; Molecular Target; Natural regeneration; Nebraska; Oncogenic; Pathway interactions; Proto-Oncogene Protein c-kit; Regulation; Resources; SAM Domain; Signal Pathway; Signal Transduction; Variant; base; career; cohort; gene network; multiple omics; novel; programs; stem cell function; success; therapeutic target

At the human GATA2 locus, disruption of two distinct cis-elements (+9.5 and -77) instigate immunodeficiency,myelodysplastic syndrome and/or acute myeloid leukemia. To define essential GATA-2 target genes, we implemented a multi-omics prioritization strategy based on sequence and molecular criteria. Among others, this analysis revealed GATA-2 regulation of Sterile Alpha Motif(SAM) Domain 14 (Samd14) expression. Mechanistic studies established that Samd14 (and the GATA-2-occupied Samd14 enhancer (Samd14-Enh)) promotes hematopoietic stem/progenitor cell (HSPC) function, facilitates regeneration in adult hematopoiesis, and is required for survival in severe anemia. Samd14-Enh promotes cell signaling through the oncogenic SCF/c-Kit pathway, conferring survival. The key mechanisms whereby Samd14 promotes SCF/c-Kit signaling and hematopoietic progenitor function are not understood. Anemia-activated Gata2 and Samd14 transcription is enhancer-dependent, establishing a foundation for defining a GATA-2 and anemia-activated gene network in regeneration, involving many intriguing and unstudied network constituents. Utilizing COBRE-sponsored facilities at UNMC and collaborations with COBRE program leaders, these aims will rigorously establish how Samd14 promotes SCF/c-Kit signaling (Aim 1), the hematopoietic function of a new SAM-domain containing gene (Aim 2), and the function of Samd14 in hematopoietic contexts (Aim 3). The proposed project is highly relevant to the overall mission of the “Nebraska Center for Molecular Target Discovery and Development”. We will define completely novel molecular mechanisms regulating an integral, oncogenic cell signaling pathway (SCF/c-Kit) with the goal of identifying therapeutic targets. The combination of Project Leader collaborations, resources provided by COBRE Cores, and the support of scientific/career mentorship will greatly enhance the impact of scientific discoveries and success of competing for R01-level funding.

在人GATA 2基因座，两个不同顺式元件（+9.5和-77）的破坏引发免疫缺陷、骨髓增生异常综合征和/或急性髓性白血病。为了确定必需的加塔-2靶基因，我们实施了基于序列和分子标准的多组学优先化策略。其中，该分析揭示了加塔-2对不育α基序（SAM）结构域14（Samd 14）表达的调节。机制研究证实，Samd 14（和加塔-2占据的Samd 14增强子（Samd 14-Enh））促进造血干/祖细胞（HSPC）功能，促进成人造血再生，并且是重度贫血中存活所必需的。Samd 14-Enh通过致癌SCF/c-Kit途径促进细胞信号传导，从而赋予存活。Samd 14促进SCF/c-Kit信号传导和造血祖细胞功能的关键机制尚不清楚。贫血激活的Gata 2和Samd 14转录是增强子依赖性的，为定义再生中的加塔-2和贫血激活的基因网络建立了基础，涉及许多有趣和未研究的网络成分。利用COBRE赞助的UNMC设施和与COBRE项目负责人的合作，这些目标将严格确定Samd 14如何促进SCF/c-Kit信号传导（Aim 1），新SAM结构域包含基因的造血功能（Aim 2）以及Samd 14在造血环境中的功能（Aim 3）。建议的项目是高度相关的整体使命的“内布拉斯加州中心的分子目标发现和发展”。我们将定义全新的分子机制，调节一个完整的致癌细胞信号通路（SCF/c-Kit），目的是确定治疗靶点。项目负责人的合作、COBRE核心提供的资源以及科学/职业导师的支持相结合，将大大增强科学发现的影响力，并成功竞争R 01级资金。