CYTOKINE-MEDIATED PATHOPHYSIOLOGY IN FANCONI ANEMIA

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DNA交联剂如丝裂霉素C （MMC）和二氧基丁烷（DEB）过敏（Auerbach 1993），骨髓衰竭，多种先天性异常，恶性肿瘤发生率显著增加。已经确定了8个互补基团（FA-A至FA-H）。最近克隆了FA- c、FA- A、FA- g组中存在缺陷的人基因。通过对小鼠的Fancc基因进行靶向突变，可以制造出Fancc缺陷小鼠。来自法国-/-小鼠的细胞对MMC和DEB过敏。然而，令人惊讶的是，虽然纯合子小鼠的生育能力下降，但没有发现明显的血液学缺陷或先天性异常。已有证据表明，某些细胞因子与范可尼贫血有关。tnf - α和ifn - γ是抑制细胞因子，可以诱导失调。造血祖细胞（fnc -/-造血祖细胞）的生长和凋亡。FANCC转基因可保护HPC免受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、甲状腺和性腺功能不足。我们假设内分泌异常是由于内分泌腺对细胞因子的异常反应，特别是tnf - α和ifn - γ。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.