Role of Lamin B Receptor in Neutrophil Maturation and Functional Activation

核纤层蛋白 B 受体在中性粒细胞成熟和功能激活中的作用

• 批准号: 7304678
• 负责人: Peter Charles Wigram Gaines
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF MASSACHUSETTS LOWELL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7304678
• 关键词: Acute Myelocytic Leukemia; Affect; Architecture; Benign; Blood Circulation; Blood capillaries; Bone Marrow; Cell Line; Cell Nucleus; Cells; Characteristics; Chemotaxis; Cholesterol Homeostasis; Chromatin Structure; Defective spinal cord development; Development; Diagnostic; Disease; Disruption; Dysmyelopoietic Syndromes; Endothelium; Fluorescence Microscopy; Foundations; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Goals; Growth; Hematopoiesis; Hematopoietic; Hereditary Disease; Heterochromatin; Human; Ichthyoses; In Vitro; Laboratories; Lamin Type B; Localized; Mediating; Migration Assay; Modeling; Molecular; Molecular Profiling; Mus; Mutation; Mycoses; Myelogenous; Myelopoiesis; Natural Immunity; Nuclear; Nuclear Envelope; Nuclear Protein; Nuclear Proteins; Nuclear Structure; Pathogenesis; Pathologic; Phenotype; Play; Process; Proteins; Respiratory Burst; Role; Signal Pathway; Stem cells; Syndrome; Testing; Thinking; Tissues; base; capillary; env Gene Products; in vivo; innovation; insight; lamin B receptor; migration; neutrophil; novel; progenitor; programs; protein expression; receptor; receptor expression; receptor function; research study; response; skeletal dysplasia

DESCRIPTION (provided by applicant): Functionally activate neutrophils are critical to the body's innate capacity to eradicate bacterial and fungal infections. During neutrophil differentiation in the bone marrow, the nucleus becomes uniquely lobulated, which is thought to facilitate the escape of neutrophils from capillary vessels into infected tissues. In certain pathologic and genetic disorders, lobulation of the neutrophil nucleus is disrupted, and the identification of hypolobulated neutrophils in circulation is an important diagnostic indicator of myelodysplasias that often precede acute myelogenous leukemias. Recent studies have demonstrated that expression of a nuclear envelope protein called the lamin B receptor (LBR) is essential to the formation of the lobulated neutrophil nucleus. However, how LBR functions to orchestrate lobulation of the neutrophil nucleus and what role it plays in neutrophil functional activation is unknown. The long-term objective of this proposal is to understand the molecular mechanisms governing the dramatic changes in nuclear architecture that occur during neutrophil differentiation and to identify the role these changes play during neutrophil functional activation. To help attain this objective, this laboratory has generated a novel progenitor cell line that carries a genetic deficiency of LBR expression and that demonstrates defective neutrophil differentiation and functional activation. The specific aims of this project are: a) to characterize the expression of nuclear envelope-associated proteins during the differentiation of LBR-deficient neutrophils, b) to determine how disruption of the nuclear architecture affects the gene expression profile of differentiating neutrophils, and c) to identify the underlying mechanisms that cause disrupted growth and functional responses of neutrophils lacking LBR expression. To achieve these specific aims, experiments will involve the use of immunostaining and fluorescence microscopy to localize expression of nuclear proteins in LBR-deficient cells. Microarrays will be screened for expression of genes in LBR-deficient neutrophils, and possible roles for LBR in mediating cholesterol metabolism in mature neutrophils will be tested. Both in vivo and in vitro transendothelial migration assays will also be used to test for LBR functions in chemotaxis. The results generated by this project will provide the foundation for future studies aimed at further understanding the close relationship between neutrophil nuclear structure and neutrophil function. The results may also offer important insight into the pathogenesis of potentially fatal hematologic disorders.

描述（由申请人提供）：功能性激活的中性粒细胞对机体消除细菌和真菌感染的先天能力至关重要。在骨髓中的中性粒细胞分化期间，细胞核变得独特地分叶状，这被认为有助于中性粒细胞从毛细血管逃逸到感染的组织中。在某些病理性和遗传性疾病中，中性粒细胞核的分叶被破坏，并且循环中的分叶减少的中性粒细胞的鉴定是通常先于急性髓性白血病的骨髓增生异常的重要诊断指标。最近的研究表明，核被膜蛋白层蛋白B受体（LBR）的表达对分叶中性粒细胞核的形成至关重要。然而，LBR如何协调中性粒细胞核的分叶以及它在中性粒细胞功能激活中起什么作用尚不清楚。这项建议的长期目标是了解在中性粒细胞分化过程中发生的核结构急剧变化的分子机制，并确定这些变化在中性粒细胞功能激活过程中发挥的作用。为了帮助实现这一目标，该实验室已经产生了一种新的祖细胞系，该细胞系携带LBR表达的遗传缺陷，并表现出缺陷的中性粒细胞分化和功能激活。该项目的具体目标是：a）表征LBR缺陷型中性粒细胞分化过程中核结构相关蛋白的表达，B）确定核结构的破坏如何影响分化型中性粒细胞的基因表达谱，以及c）确定导致LBR表达缺失型中性粒细胞生长和功能反应中断的潜在机制。为了实现这些特定的目标，实验将涉及使用免疫染色和荧光显微镜定位LBR缺陷细胞中的核蛋白表达。微阵列将筛选LBR缺陷中性粒细胞中基因的表达，并将测试LBR在成熟中性粒细胞中介导胆固醇代谢的可能作用。体内和体外跨内皮迁移试验也将用于测试趋化性中的LBR功能。本研究的结果将为进一步了解中性粒细胞核结构与功能之间的密切关系提供基础。这些结果也可能为潜在致命性血液疾病的发病机制提供重要的见解。

项目成果

Lamin B receptor regulates the growth and maturation of myeloid progenitors via its sterol reductase domain: implications for cholesterol biosynthesis in regulating myelopoiesis.

• DOI: 10.4049/jimmunol.1003804
• 发表时间: 2012-01-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Subramanian G;Chaudhury P;Malu K;Fowler S;Manmode R;Gotur D;Zwerger M;Ryan D;Roberti R;Gaines P
• 通讯作者: Gaines P