CYTOKINE-MEDIATED PATHOPHYSIOLOGY IN FANCONI ANEMIA

Fanconi贫血(FA)是一种常染色体隐性遗传病，其特征是细胞对DNA交联剂如丝裂霉素C(MMC)和二环氧丁烷(DEB)(奥尔巴赫1993)过敏，骨髓衰竭(BM)，各种先天性畸形，恶性肿瘤发病率显著增加。已鉴定出八个互补基团(FA-A至FA-H)。最近克隆了在FA-C、FA-A、FA-G组缺陷的人类基因。Fancc缺陷小鼠是通过小鼠Fancc基因的定向突变而产生的。来自法国-/-小鼠的细胞对MMC和DEB表现出超敏反应。然而，令人惊讶的是，没有检测到严重的血液缺陷或先天性异常，尽管纯合子小鼠表现出生育力下降。已收集的证据表明，某些细胞因子与范可尼贫血有关。肿瘤坏死因子-α和干扰素-γ均为抑制性细胞因子，可诱导细胞去调节。Fancc-/-造血祖细胞(HPC)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诱导的细胞凋亡。IL-6、肿瘤坏死因子-α和干扰素-γ等都是已知的介导免疫-神经-内分泌相互作用的因子。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，特别是肿瘤坏死因子-α和干扰素-γ的异常反应。拟议的项目将使用Fancc缺陷小鼠和来自内分泌腺的细胞系，以及某些细胞因子来验证这一假设。

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.