Regulation and function of nuclear envelope proteins in myelopoiesis and leukemia

核膜蛋白在骨髓细胞生成和白血病中的调节和功能

• 批准号: 7981191
• 负责人: Peter Charles Wigram Gaines
• 金额: $ 33.06万
• 依托单位: UNIVERSITY OF MASSACHUSETTS LOWELL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7981191
• 关键词: Acute Myelocytic Leukemia; Affect; Age; Binding Proteins; Blood Cells; Cell Nucleus; Cell Proliferation; Cells; Characteristics; Clinical; Development; Disease; Dysmyelopoietic Syndromes; Exhibits; Functional disorder; GA-binding protein transcription factor; Genes; Goals; Health; Hematologic Neoplasms; Hematological Disease; Hematopoietic; Hematopoietic Neoplasms; Hereditary Disease; Human; Immune system; Infection; Intermediate Filament Proteins; Kidney; Lamin Type A; Leukocytes; Life; Molecular; Morbidity - disease rate; Mus; Mycoses; Myelogenous; Myeloid Cells; Myeloid Leukemia; Myelopoiesis; Natural Immunity; Neutrophil Activation; Nuclear; Nuclear Envelope; Nuclear Structure; Patients; Pattern; Pelger-Huet Anomaly; Play; Population; Proteins; Public Health; Regulation; Role; Shapes; Structural Protein; Transcriptional Regulation; Ursidae Family; base; combinatorial; env Gene Products; innovation; insight; interest; lamin B receptor; leukemia; leukemia/lymphoma; macrophage; monocyte; mortality; neutrophil; novel; progenitor; programs; promoter; protein expression; protein function; public health relevance; response; transcription factor; vector

DESCRIPTION (provided by applicant): Neutrophils and monocytes/macrophages are essential components of the innate immune system and function to eradicate bacterial and certain fungal infections. These cells share both developmental and functional features, but they also have unique nuclear features that distinguish them from other white blood cells: neutrophils have a lobulated nucleus and monocytes bear an irregular, kidney-shaped nucleus. How these altered nuclear structures form is unclear, but deficient expression of an inner nuclear envelope protein called the lamin B receptor (LBR) causes neutrophil hypolobulation characteristic of Pelger-Hukt anomaly, and macrophages express certain nuclear envelope proteins and intermediate filament proteins called A-type lamins that are essentially lacking in other hematopoietic cells. The molecular mechanisms that create irregular nuclear features of these myeloid cells are of clinical interest because neutrophils with abnormal nuclear structure are associated with myelodysplasias that often progress to myeloid leukemias, and aberrant expression of nuclear envelope proteins has been identified in both leukemias and lymphomas. The long-term objective of this proposal is to identify the transcriptional mechanisms that drive the unique expression patterns of nuclear envelope proteins in developing myeloid cells, and to identify the roles that these proteins play in regulating myeloid cell development and their acquisition of critical functions. To achieve these objectives, the specific aims are to i) define the functions of a transcription factor, GA- binding protein (GABP), in regulating the expression of LBR, ii) identify additional targets of GABP that play important roles in orchestrating changes in nuclear structure of developing neutrophils and macrophages, and iii) manipulate the expression of NE proteins and A-type lamins in myeloid progenitors and identify effects on myeloid cell proliferation, differentiation and function. To achieve these aims, interactions of mouse Gabp with the Lbr gene promoter will be characterized, and novel mouse myeloid progenitors that lack Gabp function will be generated and analyzed for neutrophil and macrophage differentiation. Vectors that provide for, or inhibit, nuclear envelope or A-type lamin protein expression will be introduced into myeloid progenitors, and effects on differentiation, morphologic maturation and functional responses will be assessed. These studies will provide an understanding of the mechanisms that control different nuclear envelope protein expression patterns in developing myeloid cells, identify the importance of these expression patterns to myeloid differentiation, and help to explain why hematopoietic malignancies often result in aberrant nuclear structures in myeloid cells. PUBLIC HEALTH RELEVANCE: The objective of this proposal is to identify the molecular mechanisms that cause unique nuclear structural features to form in two blood cells that are critical to innate immunity, neutrophils and macrophages, and define the roles that nuclear envelope proteins play in orchestrating their nuclear features. These studies are relevant to public health because they will provide a better understanding of why aberrant nuclear structure and disrupted expression of nuclear envelope proteins are associated with hematologic malignancies, including life-threatening myelodysplasias and myelogenous leukemias.

描述（由申请人提供）：中性粒细胞和单核细胞/巨噬细胞是先天免疫系统的重要组成部分，具有根除细菌和某些真菌感染的功能。这些细胞具有共同的发育和功能特征，但它们也具有独特的核特征，将它们与其他白色血细胞区分开来：中性粒细胞具有分叶状核，单核细胞具有不规则的肾形核。这些改变的核结构是如何形成的尚不清楚，但称为核纤层蛋白B受体（LBR）的内核被膜蛋白的表达不足引起Pelger-Hukt异常的特征性中性粒细胞小叶减少，并且巨噬细胞表达某些核被膜蛋白和称为A型核纤层蛋白的中间丝蛋白，这些蛋白在其他造血细胞中基本上缺乏。产生这些骨髓细胞的不规则核特征的分子机制具有临床意义，因为具有异常核结构的中性粒细胞与通常进展为骨髓性白血病的骨髓增生异常相关，并且在白血病和淋巴瘤中均已鉴定出核膜蛋白的异常表达。该提案的长期目标是确定驱动发育中髓样细胞核膜蛋白独特表达模式的转录机制，并确定这些蛋白在调节髓样细胞发育及其获得关键功能中所起的作用。为了实现这些目标，具体的目的是i）定义转录因子GA结合蛋白（GABP）在调节LBR表达中的功能，ii）鉴定在协调发育中的嗜中性粒细胞和巨噬细胞的核结构变化中起重要作用的GABP的另外的靶标，和iii）操纵髓样祖细胞中NE蛋白和A型核纤层蛋白的表达，并鉴定对髓样细胞增殖、分化和功能的影响。为了实现这些目标，小鼠Gabp与Lbr基因启动子的相互作用将被表征，并且将产生缺乏Gabp功能的新型小鼠骨髓祖细胞并分析嗜中性粒细胞和巨噬细胞分化。将提供或抑制核膜或A型核纤层蛋白表达的载体引入髓样祖细胞中，并评估对分化、形态成熟和功能应答的影响。这些研究将提供一个了解的机制，控制不同的核包膜蛋白的表达模式，在发展中的骨髓细胞，确定这些表达模式的重要性，骨髓分化，并帮助解释为什么造血恶性肿瘤往往导致异常的核结构在骨髓细胞。 公共卫生关系：该提案的目的是确定导致独特的核结构特征在两种对先天免疫至关重要的血细胞，中性粒细胞和巨噬细胞中形成的分子机制，并定义核膜蛋白在协调其核特征中发挥的作用。这些研究与公共卫生相关，因为它们将更好地理解为什么异常的核结构和核膜蛋白表达中断与血液恶性肿瘤相关，包括危及生命的骨髓增生异常和髓性白血病。