Regulation/function of neuromedin U in hematopoiesis

神经调节肽 U 在造血过程中的调节/功能

• 批准号: 7469595
• 负责人: SUSAN SHETZLINE
• 金额: $ 13.25万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-15 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7469595
• 关键词: Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Area; Binding; Binding Sites; Blood; Blood Cells; Bone Marrow; COS-7 Cell; Calcium ion; Cell Differentiation process; Cell Line; Cell Lineage; Cell Proliferation; Cell physiology; Cells; Cellular biology; Consensus; Data; Development; Dominant-Negative Mutation; Engineering; Erythroid; FOS gene; Family; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gi-Go; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Hematopoiesis; Hematopoietic; Human; Inositol; Inositol Phosphates; K-562; K562 Cells; Light; MYB gene; Malignant - descriptor; Mediating; Megakaryocytes; Mutate; Myelogenous; Myeloid Cells; Neuromedin U; Pathway interactions; Patients; Pertussis Toxin; Phospholipase C; Phosphotransferases; Physiological; Play; Process; Protein Kinase C; Proto-Oncogene Proteins c-myb; Regulation; Research Personnel; Research Training; Role; Signal Transduction; Stem cells; Tamoxifen; Testing; Transcription Factor AP-1; Transcriptional Regulation; autocrine; base; bone marrow hyperplasia; cell growth; human GPRC5C protein; insight; leukemia; leukemogenesis; neuromedin U receptor; novel; promoter; receptor; transcription factor

DESCRIPTION (provided by applicant): Hematopoiesis is the formation of specific cell lineages in the blood through proliferation and differenatiation of pluripotent hematopoietic cells. The proto-oncogene c-myb encodes a transcription factor expressed predominantly in hematopoietic cells and plays a critical role in their proliferation, survival, and differentiation. Our preliminary data has identified neuromedin U (NmU) as a novel Myb gene target in K562 cells that were engineered to express a tamoxifen inducible dominant negative Myb (MERT). We also demonstrate that both c-myb and NmU are elevated in cell lysates from acute myeloid leukemia (AML) patients compared to normal donors. Cell lysates from AML patients and normal donors also express NmU receptor type-1 (NMUR1), a G-protein coupled receptor. In addition, exposing our K562 cell lines to NmU promoted cell proliferation and induced intracellular Ca+2 flux. Based on these observations, we hypothesize that NmU plays a key physiological role in hematopoietic cells. To test this hypothesis, I will study the regulation and function of NmU in hematopoietic cells with the following specific aims: Aim #1 - Investigate NmU-mediated signal transduction in hematopoietic cells. To begin to unravel the mechanism of NmU action in hematopoietic cells, I will examine the ability of NmU to activate phospholipase C and protien kinase C. Aim #2 - Examine the transcriptional regulation of NmU in hematopoietic cells. This aim proposes studies to evaluate the role of Myb and c-fos in modulating NmU gene expression, because these motifs have been identified in the putative NmU promoter. Aim #3 - Determine the importance of NmU during hematopoiesis. This aim will focus on the ability of NmU to promote proliferation of hematopoietic cells through an autocrine loop and determine the effect NmU has on differentiating hematopoietic cells along the erythroid and megakaryocyte lineages. The proposed didactic training and research plan will facilitate the transition of this candidate into a productive independent investigator in the areas of hematopoiesis and stem cell biology.

描述（由申请人提供）： 造血是通过多能造血细胞的增殖和分化在血液中形成特定细胞谱系。原癌基因 c-myb 编码主要在造血细胞中表达的转录因子，并在造血细胞的增殖、存活和分化中发挥关键作用。我们的初步数据已确定神经调节肽 U (NmU) 是 K562 细胞中的新型 Myb 基因靶标，该细胞经过改造可表达他莫昔芬诱导型显性失活 Myb (MERT)。我们还证明，与正常供体相比，急性髓系白血病 (AML) 患者的细胞裂解物中 c-myb 和 NmU 均升高。来自 AML 患者和正常供体的细胞裂解物也表达 NmU 1 型受体 (NMUR1)，一种 G 蛋白偶联受体。此外，将我们的 K562 细胞系暴露于 NmU 促进细胞增殖并诱导细胞内 Ca+2 流动。基于这些观察，我们假设 NmU 在造血细胞中发挥着关键的生理作用。为了验证这一假设，我将研究 NmU 在造血细胞中的调节和功能，具体目标如下： 目标 #1 - 研究造血细胞中 NmU 介导的信号转导。为了开始阐明 NmU 在造血细胞中的作用机制，我将检查 NmU 激活磷脂酶 C 和蛋白激酶 C 的能力。目标 #2 - 检查 NmU 在造血细胞中的转录调节。该目的提出研究评估 Myb 和 c-fos 在调节 NmU 基因表达中的作用，因为这些基序已在推定的 NmU 启动子中得到鉴定。目标 #3 - 确定 NmU 在造血过程中的重要性。该目标将重点关注 NmU 通过自分泌环促进造血细胞增殖的能力，并确定 NmU 对沿红系和巨核细胞谱系分化造血细胞的影响。拟议的教学培训和研究计划将促进该候选人转变为造血和干细胞生物学领域富有成效的独立研究者。