CYTOKINE-MEDIATED PATHOPHYSIOLOGY IN FANCONI ANEMIA

范可尼贫血中细胞因子介导的病理生理学

• 批准号: 6211564
• 负责人: MING CHEN
• 金额: $ 4.63万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-21 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6211564
• 关键词: adrenocorticotropic hormone; antisense nucleic acid; apoptosis; cellular pathology; congenital aplastic anemia; disease /disorder model; endocrine disorder; endocrinology; follicle stimulating hormone; gene mutation; genetically modified animals; hematopoietic stem cells; hormone biosynthesis; human tissue; hypothalamus; interferon gamma; interleukin 6; laboratory mouse; luteinizing hormone; oligonucleotides; polymerase chain reaction; somatotropin; thyrotropin; tissue /cell culture; tumor necrosis factor alpha

Fanconi anemia (FA) is an autosomal recessive disorder characterized by cellular hypersensitivity to DNA crosslinking agents such as mitomycin C (MMC) and diepoxybutane (DEB) (Auerbach 1993), bone marrow (BM) failure, diverse congenital anomalies, and a marked increased in the incidence of malignancies. Eight complementation groups (FA-A through FA-H) have been identified. The human genes defected in the FA-C, FA- A FA-G groups were recently cloned. Fancc-deficient mice have been created by targeted mutations of the murine Fancc gene. Cells from France -/- mice showed hypersensitivity to MMC and DEB. Surprisingly, however, no gross hematologic defects or congenital anomalies were detected, although the homozygous mice showed decreased fertility. Evidence has been collected indicating that certain cytokines are involved in Fanconi anemia. TNF-alpha and IFN-gamma are inhibitory cytokines that can induced deregulated. Progenitor growth and apoptosis in Fancc-/- hematopoietic progenitor cells (HPC). FANCC transgene protected HPC FANCC transgene protected HPC from Fas-mediated apoptosis. IL-6, TNF-alpha and IFN-gamma, among others, are known to mediate immune-neuro-endocrine interactions. More recently, multiple endocrine abnormalities were discovered in FA patients, including deficiencies in growth hormone, thyroid and gonads function. We hypothesize that the endocrine abnormalities be due to aberrant response to cytokines, particularly TNF-alpha and IFN-gamma, in the endocrine glands. The proposed project will use Fancc-deficient mice and cell lines derived from endocrine glands, along with certain cytokines, to test this hypothesis.

范可尼贫血（FA）是一种常染色体隐性遗传病，其特征是细胞对丝裂霉素 C（MMC）和二环氧丁烷（DEB）等 DNA 交联剂过敏（Auerbach 1993）、骨髓（BM）衰竭、多种先天性异常以及恶性肿瘤发病率显着增加。已确定八个互补组（FA-A 至 FA-H）。 FA-C、FA-A、FA-G 组中缺陷的人类基因最近被克隆。 Fancc 缺陷小鼠是通过小鼠 Fancc 基因的定向突变而产生的。来自 France -/- 小鼠的细胞对 MMC 和 DEB 表现出超敏反应。然而，令人惊讶的是，尽管纯合子小鼠表现出生育能力下降，但没有检测到明显的血液学缺陷或先天性异常。已收集的证据表明某些细胞因子与范可尼贫血有关。 TNF-α 和 IFN-γ 是抑制性细胞因子，可诱导失调。 Fancc-/- 造血祖细胞 (HPC) 中的祖细胞生长和凋亡。 FANCC 转基因保护 HPC FANCC 转基因保护 HPC 免受 Fas 介导的细胞凋亡。已知 IL-6、TNF-α 和 IFN-γ 等可介导免疫-神经-内分泌相互作用。最近，在 FA 患者中发现了多种内分泌异常，包括生长激素、甲状腺和性腺功能缺陷。我们假设内分泌异常是由于内分泌腺对细胞因子，特别是 TNF-α 和 IFN-γ 的异常反应所致。拟议的项目将使用 Fancc 缺陷小鼠和源自内分泌腺的细胞系以及某些细胞因子来检验这一假设。