T1alpha in type I cell formation, regulation & function

描述(由申请人提供)： 肺泡扩大的气体交换面的形成 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。类型1细胞高度 专门用于气体交换，约占肺泡表面的95%。 这些大的、高度衰减的细胞形成失败或延迟会损害 新生儿和成人受损肺的气体交换。类型1单元格是 异常容易受到各种因素的伤害，包括高 治疗用来支持早产儿的氧气浓度； 因此，了解如何控制和加速1型细胞的形成和 差异化是本研究的一个重要的长期目标。三 提出了具体的目标。首先是刻画异常的特征 慢性支气管炎动物外周肺上皮细胞增殖的观察 T1pha是一种1型细胞特异性基因，靶向缺失。而正常 外周肺细胞在出生前后暂时停止分裂， 在这些空洞的动物身上，繁殖仍在继续。拟议中的研究将检验 T1a的表达与细胞增殖和增殖的关系 外周肺中的分化，并将确定候选细胞周期 导致持续扩散的调控基因。T1a基因将 以检测异常增殖反应是否 与年龄无关或仅见于胎儿/新生儿肺。《特定目标2》将测试 启动子甲基化在限制基因特异性表达中的作用 上皮细胞类型，以T1a和SP-B为代表的1型和11型 细胞基因。具体目标3将确定起源细胞和 T1a在新生大鼠肺内植入骨髓源性细胞中的作用 它们显示了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型的调节 细胞，这是肺泡生物学中一个鲜为人知的领域，但它是至关重要的 为成功的肺部发育干杯。

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.