Growth Factor Protection in Acute Lung Injury

描述（由申请人提供）：急性肺损伤预后不良，病因多样。许多促发因素已被确定，但问题仍然存在的病理生理机制控制这种复杂的条件和它们的关系，治疗策略。以上皮损伤和表面活性剂功能丧失为标志，急性肺损伤可导致生长因子活化，包括转化生长因子-α（TGF α）和TGF β的活化。这些生长因子反过来控制增殖和参与分化功能的基因的转录。以前，携带TGF α的基因位点与急性肺损伤有关，并且TGF α转基因小鼠被从急性肺损伤中拯救出来。其他数据表明，这些影响可能是通过位于呼吸道上皮细胞的EGFR介导的。已经产生了条件性TGF α转基因小鼠，以允许详细研究这种生长因子在肺损伤中的时间作用。最近，我们发现在我们的急性肺损伤模型中，TGF β被释放，并且许多TGF β反应性转录物被改变。我们的中心假设是TGF α和TGF β信号通路之间的相互作用通过改变对肺功能至关重要的转录程序来决定急性肺损伤的存活率和后遗症。为了进一步评估TGF α和TGF β在急性肺损伤中的作用，我们建议操纵TGF α信号传导并监测TGF β信号传导的后果。该提案的具体目标是：1）鉴定负责TGF α/EGFR介导的急性肺损伤保护的分子机制，2）评价急性肺损伤期间TGF α诱导和TGF α/EGFR信号传导的治疗功效，并确定肺纤维化是否是保护的必然后果，和3）确定调节关键基因表达的TGF α和TGF β相互作用的遗传机制，重点是控制Sftpb启动子反式激活的顺式作用元件。这项研究具有创新性，因为它将直接评估TGF α/EGFR信号传导的潜在治疗益处以及TGF α与TGF β在急性肺损伤中的可能相互作用。在这个项目完成后，我们期望：1）确定由TGF α调节的导致急性肺损伤保护的转录事件，2）更好地理解TGF β在急性肺损伤中的功能，3）确定肺纤维化是否是急性肺损伤期间激活TGF α/EGFR信号传导的不良后果。这些研究的预期影响将是基于证据的科学验证或反驳针对TGF α/EGFR信号传导的疗法可被考虑用于治疗急性肺损伤的可能性。

DESCRIPTION (provided by applicant): Acute lung injury has a poor prognosis and a diverse etiology. Numerous precipitating factors have been identified, yet questions remain about the pathophysiological mechanisms controlling this complex condition and their relationship to therapeutic strategies. Marked by epithelial damage and loss of surfactant function, acute lung injury can lead to growth factor activation, including activation of transforming growth factor-alpha (TGFalpha) and TGFbeta. These growth factors, in turn, control proliferation and the transcription of genes involved in differentiated function. Previously, a genetic locus that harbors TGFalpha was linked to, and TGFalpha transgenic mice were rescued from, acute lung injury. Additional data imply that these effects may be mediated through EGFR located on respiratory epithelial cells. Conditional TGFalpha transgenic mice have been generate to permit detailed investigations of the temporal role of this growth factor in lung injury. Recently, we found TGFbeta is released, and many TGFbeta responsive transcripts are altered in our model of acute lung injury. Our central hypothesis is that the interplay between TGFalpha and TGFbeta signaling pathways determines survival and the sequelae resulting from acute lung injury by altering transcriptional programs critical to lung function. To further assess the role of TGFalpha and TGFbeta in acute lung injury, we propose to manipulate TGFalpha signaling and monitor the consequences on TGFbeta signaling. The Specific Aims of this proposal seek to: 1) Identify the molecular mechanisms responsible for TGFalpha/EGFR mediated protection in acute lung injury, 2) Evaluate the therapeutic efficacy of TGFalpha induction and TGFalpha/EGFR signaling during acute lung injury and determine whether pulmonary fibrosis is a necessary sequela as a consequence of protection, and 3) Determine the genetic mechanisms of TGFalpha and TGFbeta interactions that modulate critical gene expression, focusing on the cis-acting elements that control Sftpb promoter transactivation. This research is innovative because it will directly evaluate the potential therapeutic benefits of TGFalpha/EGFR signaling and the possible interactions of TGFalpha with TGFbeta in acute lung injury. At the completion of this project, we expect to: 1) Identify the transcriptional events modulated by TGFalpha that leads to protection from acute lung injury, 2) Gain a better understanding of how TGFbeta functions in acute lung injury, and 3) Determine whether pulmonary fibrosis is an untoward consequence of activating TGFalpha/EGFR signaling during acute lung injury. The anticipated impact of these studies would be an evidence-based scientific verification or refutation of the likelihood that therapeutics directed at TGFalpha/EGFR signaling could be considered for the treatment of acute lung injury.