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.
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.
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