T1alpha in type I cell formation, regulation & function

描述（由申请人提供）： 肺泡形成广泛的气体交换表面 1型细胞可能是肺发育后期最重要的事件。 拟议的研究解决了有关分子调控的问题， 这些细胞的表型、功能和形成。1型细胞高度 专门用于气体交换并形成约95%的肺泡表面。 这些大的、高度减毒的细胞的形成失败或延迟， 新生儿和成人受伤肺部的气体交换。1型细胞是 异常容易受到各种因素的伤害，包括高 用于支持早产儿治疗的氧气浓度; 因此，了解如何控制和加速1型细胞的形成， 差异化是本研究的一个重要长期目标。三 提出了具体目标。一是定性异常 在患有肺结核的动物中观察到外周肺上皮细胞的增殖， 靶向缺失T1 α，一种1型细胞特异性基因。而正常 外周肺细胞在出生时暂时停止分裂， 在这些无效动物中继续增殖。拟议的研究将测试 T1 a表达与细胞增殖的关系， 在外周肺分化，并将确定候选细胞周期 调节基因的持续增殖。T1 a基因 在成年人中被删除，以测试异常增殖反应是否 与年龄无关或仅限于胎儿/新生儿肺。具体目标2将测试 启动子甲基化在限制基因表达中的作用 上皮细胞类型，使用T1 a和SP-B作为代表性1型和11型 细胞基因具体目标3将确定起源细胞和 T1 a在新生儿肺中骨髓源性细胞的植入中的作用， 它们显示1型细胞的形态和分子表型。这些 研究将使用最先进的方法来探索1型糖尿病的调节。 细胞，肺泡生物学的一个知之甚少的领域，但一个是至关重要的 成功的肺部发育。

DESCRIPTION (provided by applicant): Formation of the extensive gas exchange surface by alveolar type 1 cells is perhaps the most important event in late lung development. The proposed studies address questions about regulation of the molecular phenotype, function, and formation of these cells. Type 1 cells are highly specialized for gas exchange and form about 95% of the alveolar surface. Failed or delayed formation of these large, highly attenuated cells impairs gas exchange in neonates and in injured lungs of adults. Type 1 cells are unusually susceptible to injury by various agents including the high concentrations of oxygen used therapeutically to support premature infants; thus, understanding how to control and accelerate type 1 cell formation and differentiation is an important long-term goal of this research. Three Specific Aims are proposed. The first is to characterize the abnormal proliferation of peripheral lung epithelial cells observed in animals with a targeted deletion in T1alpha, a type 1 cell specific gene. Whereas normal peripheral lung cells temporarily stop dividing around the time of birth, proliferation continues in these null animals. The proposed studies will test the relationships between T1a expression and cell proliferation and differentiation in the peripheral lung and will identify candidate cell cycle regulatory genes that account for sustained proliferation. The T1a gene will be deleted in adults to test whether the abnormal proliferative response is age-independent or unique to fetal/newborn lung. Specific Aim 2 will test the role of promoter methylation in restricting gene expression to specific epithelial cell types, using T1a and SP-B as representative type 1 and type 11 cell genes. Specific Aim 3 will identify the cell of origin and the role of T1a in the engraftment of bone marrow-derived cells in neonatal lung where they display the morphology and molecular phenotype of type 1 cells. These studies will use state-of-the-art methods to explore regulation of type 1 cells, a poorly understood area of alveolar biology, but one that is critical to successful lung development.