Molecular Targets for Drug Discovery in IPF

描述（由申请人提供）：IPF是一种致死性疾病，由于成纤维细胞及其结缔组织产物在肺泡壁的持续积累而导致窒息死亡。由于每个肺泡都受到疾病过程的影响，因此存在先天免疫、上皮细胞死亡和纤维增殖的有害协同作用，类似于损伤中观察到的事件——除了IPF，损伤永远不会愈合。为了阻止这种进行性疾病，我们将重点放在纤维增殖过程本身及其关键细胞成分肌成纤维细胞上。来自纤维化病变的肌成纤维细胞与那些来自正常愈合的表皮和内脏伤口的肌成纤维细胞之间的一个显著区别是，与正常的肌纤维细胞相比，纤维化肌成纤维细胞不能及时发生凋亡。因此，我们假设导致异常肌成纤维细胞持续存在的凋亡级联的调节成分将成为抗纤维化药物发现的候选分子靶点。我们的目标是开发旨在破坏IPF肺中肌成纤维细胞进行凋亡的病理失败的治疗方法，并在纤维化病变中恢复对促凋亡线索的生理敏感性。我们计划通过两个具体目标来实现我们的目标。目的1：合成并评估击中真核翻译起始因子4E （eIF4E）帽结合袋的化合物，eIF4E是控制编码成纤维细胞凋亡关键调节因子mRNA翻译的真正分子靶点。目的2：探索沿细胞外基质调节的凋亡通路发现抗纤维化药物的潜在分子靶点。如果成功，我们的工作将证实或反驳eIF4E作为抗纤维化治疗靶点，并有可能导致新的IPF特异性分子靶点的鉴定，用于抗纤维化药物的发现。

DESCRIPTION (provided by applicant): IPF is a lethal disease leading to death by suffocation due to the relentless accumulation of fibroblasts and their connective tissue products in the alveolar wall. As each alveolus is afflicted by the disease process, there is a pernicious collaboration of innate immunity, epithelial cell death and fibroproliferation simulating the events observed in injury -- except in IPF the injury never heals. In an effort to arrest this progressive disease, here we focus on the fibroproliferative process itself, and its key cellular constituent the myofibroblast. One striking difference between myofibroblasts from fibrotic lesions and those from integumentary and visceral wounds that heal normally is the failure of fibrotic myofibroblasts - in contrast to their normal counterparts - to undergo timely apoptosis. Therefore, we hypothesize that regulatory constituents of the apoptotic cascade that result in aberrant myofibroblast persistence will be candidate molecular targets for antifibrotic drug discovery. Our objective is to develop therapeutics designed to undermine the pathological failure of myofibroblasts in the IPF lung to undergo apoptosis, and restore physiological sensitivity to proapoptotic cues in evolving fibrotic lesions. We plan to achieve our objective through 2 specific aims. Aim 1: Synthesize and evaluate compounds hitting the cap-binding pocket of eukaryotic translation initiation factor 4E (eIF4E), a bonafide molecular target controlling the translation of mRNA encoding key regulators of fibroblast apoptosis. Aim 2: Explore potential molecular targets for antifibrotic drug discovery along apoptotic pathways regulated by the extracellular matrix. If successful, our work will confirm or refute eIF4E as an antifibrotic therapeutic target, and potentially lead to the identification of new IPF specific molecular targets for antifibrotic drug discovery.