TGF Beta Receptor Dynamics

项目负责人/主要研究者（最后、最后、中间）：Leof，Edward，B 项目总结（见说明）： 转化生长因子β（TGF-β）生物学的一个中心矛盾是，同一个生长因子如何能够 诱导诸如生长刺激（即，间充质细胞）和生长抑制（即， 上皮细胞）？考虑到TGF-β在许多正常和病理状况中的关键作用， 如果我们希望制定具体的干预战略，解决这一问题至关重要。为此我们 我一直在研究细胞对TGF-β的反应依赖于 交通和信号机械的综合作用。为了支持这一建议，我们 确定（i）在极化的上皮细胞中，TGF-β受体运输到基底外侧域，邻近基底外侧域， （ii）哺乳动物逆转录复合物特异性维持II型TGF-β受体 通过控制再循环内体到质膜的传递，通过网格蛋白、EEA 1和 Rab 11阳性区室;（iii）分选连接蛋白9（SNX 9），一种已知的运输蛋白，在Rab 11阳性区室中具有新的作用。 TGF-β信号转导下游的规范血浆膜的行动;（iv）一个独特的机制，已被证实， 通过其可以控制TGF-β信号传导的特异性并随后用于治疗 依赖于Smad 3的疾病;（v）促纤维化TGF-β反应需要PDGF的协同作用 和ErbB受体酪氨酸激酶;以及，最重要的是，（vi）利用肺纤维化的治疗模型， 提供了临床前数据，证明肺功能的生理参数可以通过以下方法稳定 靶向多种TGF-β调节途径。我们建议使用各种方法来扩展这些发现， 生物化学、生物学和遗传学方法。第一，受体元件和细胞因子控制 将定义TGF-β受体运输以及逆转录酶在TGF-β刺激的EMT/迁移中的作用。 由于许多疾病是由于将蛋白质分类或转运到特定细胞的能力缺陷引起的， 区域，表征操作性反式作用因子提供了改变细胞凋亡的潜在机制。 第二，SNX 9在调节Smad 3依赖性表型（包括肺细胞）中的作用。 将确定纤维化和胶质母细胞瘤进展。在美国， 发达的wortd是由于某种慢性纤维增生性疾病，和中位数 目前放化疗的胶质母细胞瘤的无进展和sun/ival为~7和15个月， 显然需要采取新的办法。 相关性（参见说明）： TGF-β是一种对人体健康有益或有害的蛋白质。虽然它刺激细胞的能力 生长对于正常的伤口愈合是重要的，当不受抑制时，许多器官的功能可能会受到影响。 被疤痕破坏（即，纤维化）形成。相反地，TGF-β的生长抑制作用在肿瘤的生长中是关键的。 预防癌症拟议的研究将确定/表征可用于增加 或减少这些反应。

ProgramDirector/PrincipalInvestigator(Last,Rrst,Middle):Leof,Edward,B PROJECT SUMMARY (See Instmctions): A central paradox in transforming growth factor beta (TGF-p) biology is how the same growth ^ctor can induce such divergent responses as growth stimulation (i.e., mesenchymal cells) and growth inhibition (i.e., epithelial cells)? Considering the pivotal role TGF-^ has in a number of nomial and pathological conditions, addressing that issue is fundamental if we hope to develop specific intervention strategies. To that end, we have been investigating the general hypothesis that the cellular response to TGF-¿ is dependent upon an integrated action ofthe trafficldng and signaling machinery. In support of that proposal, we have detemiined that (i) in polarized epithelial cells TGF-p receptors traffic to the basolateral domain, adjacent to the junctional complex; (ii) the mammalian retromer complex specifically maintains type II TGF-p receptor polarity by controlling recycling endosome to plasma membrane delivery by way of clathrin, EEA1 and Rab11 positive compartments; (iii) sorting nexin 9 (SNX9), a known trafficking protein, has a new role in TGF-p signaling downstream of its canonical plasma membriane action; (iv) an unique mechanism has been defined by which specificity in TGF-p signaling can be controlled and subsequently exploited to treat diseases dependent upon Smad3; (v) profibrotic TGF-p responses require the cooperative action of PDGF and ErbB receptor tyrosine kinases; and, most importantly, (vi) utilizing a treatment model of lung fibrosis, provided preclinical data documenting that physiologic parameters of lung function can be stabilized by targeting multiple TGF-p regulated pathways. We propose to extend these findings using a variety of biochemical, biological, and genetic approaches. First, the receptor elements and cellular factors controlling TGF-p receptor trafficking as well as the role of retromer in TGF-p stimulated EMT/migration will be defined. As a number of diseases result from defects in the ability to sort or transport proteins to defined cellular locales, characterizing the operative trans-acting factors provides potential mechanisms to alter the cellular response to TGF-p. Second, the role of SNX9 in regulating Smad3-dependent phenotypes including lung fibrosis and glioblastoma progression will be determined. In that upwards of 45% of all deaths in the developed wortd are attributed to some sort of chronic fibroproliferative disorder, and the median progression-free and sun/ival for glioblastoma with current chemoradiation is ~7 and 15 months, respectively, new approaches are clearly needed. RELEVANCE (See instructions): TGF-p is a protein that can be either helpful or harmful to human health. While its ability to stimulate cell growth is important for normal wound healing, when unchecked the function of many organs can be disrupted by scar (i.e., fibrosis) formation. Conversely, the growth inhibitory actions of TGF-p are critical in preventing cancer. The proposed studies will identify/characterize targets that can be used to either increase or decrease these re.sDnnses.