CYTOKINE-MEDIATED PATHOPHYSIOLOGY IN FANCONI ANEMIA

范可尼贫血（FA）是一种常染色体隐性遗传疾病，其特征为细胞对DNA交联剂（如丝裂霉素C（MMC）和二环氧丁烷（DEB））超敏（奥尔巴赫1993）、骨髓（BM）衰竭、各种先天性异常和恶性肿瘤发生率显著增加。已鉴定出八个互补组（FA-A至FA-H）。最近克隆了FA-C、FA-A、FA-G组中的人类基因缺陷。Fancc缺陷小鼠是通过鼠Fancc基因的靶向突变产生的。法国-/-小鼠的细胞表现出对MMC和DEB的超敏反应。然而，令人惊讶的是，尽管纯合子小鼠表现出生育力下降，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，某些细胞因子参与范可尼贫血。TNF-α和IFN-γ是可诱导失调的抑制性细胞因子。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免于Fas介导的凋亡。已知IL-6、TNF-α和IFN-γ等介导免疫-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、甲状腺和性腺功能的缺乏。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。该项目将使用Fancc缺陷小鼠和来自内分泌腺的细胞系，沿着某些细胞因子，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.