TGF BETA SIGNALING IN LUNG MORPHOGENESIS, INJURY AND REPAIR

假设：（1）过度的TGF-β信号传导破坏了有序的 通常指导肺形态发生的时空分子线索 和细胞分化，如暴露于发育中的 肺升高的环境氧气;因此（2）调节过量 TGF-β信号传导将改善肺损伤并增强肺组织的修复。 肺发育 特殊目的： 1. 为了确定增加的环境氧气对TGF-β的影响， 在出生后和成人体内的产生、激活和信号传导 鼠肺 2. 确定TGF-β过度表达的空间效应 使用TGF-β的潜伏或活性（突变）形式的肽 重组腺病毒载体在离体小鼠胚胎肺中的表达 文化 3. 为了确定TGF-β肽的过度表达对细胞增殖的影响， 新生小鼠在体肺泡形成的实验研究 TGF-β重组腺病毒载体气管内给药。 4. 确定上皮TGF-β受体信号在体内的作用 转导分子对肺形态发生、损伤和修复的影响 活性与C-末端截短阴性的转基因表达 使用hSP-C肺上皮特异性启动子的Smads。 5. 为了确定下调TGF-β信号的策略是否 包括免疫扰动、竞争肽和特异性抗血清 寡脱氧核苷酸可以改善过量的 TGF-β信号传导。 对人类健康的重要性：拟议的研究将确定 过度的TGF-β信号是否在发展中起着不利的作用， 并将确定新的治疗策略的可行性 调节TGF-β信号传导。 慢性肺病的防治 早产儿的疾病可能成为可能。

Hypothesis: (1) excess TGF-beta signaling disrupts the orderly temporo-spatial molecular cues that normally instruct lung morphogenesis and cytodifferentiation as seen following exposure of the developing lung to elevated ambient oxygen; therefore (2) modulationof excess TGF-beta signaling will ameliorate lung injury and augment repair of the developing lung. Speicifc Aims: 1. To determine the impact of increased ambient oxygen on TGF-beta production, activation and signaling in vivo in postnatal and adult murine lung. 2. To determine the spatial effects of over-expression of TGF-beta peptides ineither latent or active (mutated) forms using TGF-beta recombinant adenoviral vectors in embryonic mouse lung in ex vivo culture. 3. To detemine the effects of TGF-beta peptide over-expression on alveolarizationin neonatal mouse lung in vivo byintra-nasal or intratracheal administration of TGF-beta recombinant adenoviral vectors. 4. To determine the in vivo role of epithelial TGF-beta receptor signal transduction molecules onlung morphogenesis, injury and repair by transgenic expression of active versus C-terminally truncated negative Smads using the hSP-C lung epithelium specific promoter. 5. To determine whether strategies to down-modulate TGF-beta signaling including immunoperturbation, competing peptides and speicifc antisnse oligodeoxynucleotides can ameliorate the adverse impact of excess TGF-beta signaling. Significance to Human Health: the propsoed studies will determine whether excess TGF-beta signaling plays an adverse role in developing lung and will determine the feasibility of novel therapeutic strategies tomodulate TGF-beta signaling. Prevention andtreatment of chronic lung disease in premature infants may become possible.