EPITHELIAL GROWTH FACTORS IN ENVIRONMENTAL LUNG DISEASE

描述：这项建议侧重于吸入性疾病的分子机制。 无机颗粒诱导的纤维增生性肺疾病(FLD)。这个 正在研究的中心假设是间质纤维化肺 疾病由间充质细胞生长因子、PDGF、转化生长因子-α、 转化生长因子-β和肿瘤坏死因子-α，由细胞合成和分泌 肺损伤所致的细支气管肺泡上皮细胞。四个具体的 给出了检验这一假说的目的。在目标1中，两个品系的小鼠 抗吸入石棉的纤维化作用被用来 确定基因的时间和解剖表达是否与生长 肺泡上皮细胞的因素与耐药性有关。在AIM 2 从这些相同品系的小鼠身上分离出肺泡上皮细胞以 确定石棉抗性表型是否在体外保持。在……里面 目的3首席研究员建议重点研究增殖细胞核抗原在卵巢癌中的表达 能够形成纤维化病变的细胞与来自耐药细胞的比较 老鼠品系。在AIM中，4只转基因小鼠在体内过表达人PDGF-B 细支气管-肺泡上皮与自发发育 肺内纤维增生性异常将与 石棉耐药菌株以确定后代是否增加 对石棉的敏感性。这可能与PDGF-B参与纤维化肺有关 并针对这种生长因子进行抗体或基因治疗。

DESCRIPTION: This proposal focuses on the molecular mechanisms for inhaled inorganic particle-induced fibroproliferative lung disease (FLD). The central hypothesis being examined is that interstitial fibrogenic lung disease is mediated by the mesenchymal cell growth factors, PDGF, TGF-alpha, TGF-beta and TNF-alpha, that are synthesized and secreted by the bronchiolar-alveolar epithelium as a result of lung injury. Four specific aims are given to test this hypothesis. In aim 1, two strains of mice resistant to the fibrogenic effects of inhaled asbestos are used to determine if the temporal and anatomic expression of the genes and growth factors by the alveolar epithelium correlates with resistance. In aim 2 alveolar epithelial cells are isolated from these same mice strains to determine if the asbestos-resistance phenotype is maintained in vitro. In aim 3 the principal investigator proposes to focus on PCNA expression in cells capable of forming fibrogenic lesions versus those from resistant mouse strains. In aim 4 transgenic mice overexpressing human PDGF-B within the bronchiolar-alveolar epithelium and spontaneously developing fibroproliferative abnormalities in the lung will be crossed with asbestos-resistant strains to determine if the offspring have increased susceptibility to asbestos. This would implicate PDGF-B in fibrogenic lung disease and target this growth factor for antibody or gene therapy.