TGF Beta Receptor Dynamics

TGF β 受体动力学

• 批准号: 8463550
• 负责人: EDWARD B LEOF
• 金额: $ 32.87万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8463550
• 关键词: 4-ethoxymethylene-2-phenyl-2-oxazoline-5-one; Abbreviations; Address; Affect; Amino Acid Motifs; Amino Acids; Amphiregulin; Binding; Biochemical; Biological; Biology; Carrier Proteins; Cell Nucleus; Cell membrane; Cells; Cicatrix; Complex; Cytoplasmic Tail; Data; Defect; Destinations; Disease; Disintegrins; Documentation; Dominant-Negative Mutation; Drosophila genus; Dynamin; Endocytosis; Epidermal Growth Factor; Epiregulin; Epithelial; Epithelial Cells; Family; Family member; Fibrosis; Genetic Transcription; Growth; Growth Factor; Health; Heparin Binding; Homeostasis; Human; Immunoprecipitation; In Vitro; Indium; Intervention; Kidney; Length; Ligands; Locales; Malignant Neoplasms; Mediating; Mediator of activation protein; Membrane; Mesenchymal; Metalloproteases; Modeling; Normal tissue morphology; Nuclear; Organ; Orthologous Gene; Pathologic Processes; Phenotype; Phosphorylation; Platelet-Derived Growth Factor; Population; Prevention; Proteins; Publishing; Rattus; Regulation; Research Design; Role; Signal Transduction; Sorting - Cell Movement; Surface; T2R taste receptors; Tail; Testing; Tissues; Trans-Activators; Transcriptional Regulation; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Transforming Growth Factors; Tropism; Ureteral obstruction; Vacuolar Protein Sorting; Wing; Work; Wound Healing; basolateral membrane; betacellulin; cell growth; connective tissue growth factor; epigen; granulocyte; heparin-binding EGF-like growth factor; member; monocyte colony stimulating factor; nexin; paracrine; prevent; protein transport; public health relevance; receptor; receptor binding; response; trafficking

DESCRIPTION (provided by applicant): A central paradox in transforming growth factor beta (TGF-?) biology is how the same growth factor 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 normal 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 of the trafficking and signaling machinery. In support of that proposal, we provide evidence that (i) a unique motif in the type II TGF-? receptor (T2R) regulates basolateral membrane delivery via a non-canonical mechanism; (ii) sorting nexin 9 (SNX9) distinguishes Smad3-dependent responses from Smad2; and (iii) the induction of ErbB family members is critical to the mesenchymal cell phenotype regulated by TGF-?. In this competing renewal we will extend these concepts using a variety of biochemical, biological, and morphologic approaches. First, we will determine the role of the mammalian retromer complex in regulating TGF-?R trafficking. 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-?. Second, the mechanism(s) by which SNX9 controls Smad3 transcriptional activity will be characterized. Given that the majority of Smad-dependent transcription is mediated via Smad3, these studies raise the possibility that intervention strategies can be developed to enhance or diminish Smad3-specific responses. Third, the role of EGF family members in pro-fibrotic TGF-? signaling will be defined. Since TGF-? is regulated by the concerted action of both direct and indirect mediators, our finding that ErbB ligands are fundamental for the pro-fibrotic phenotype seen following addition of TGF-? suggests new paradigms to the genesis of tissue fibrosis.

描述（由申请人提供）：转化生长因子β（TGF-？）生物学是相同的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-的关键作用？在许多正常和病理条件下，如果我们希望制定具体的干预战略，解决这个问题是至关重要的。为此，我们一直在调查的一般假设，细胞反应TGF-？依赖于贩运和信号机制的综合行动。在支持这一建议，我们提供的证据表明，（i）在II型TGF-？受体（T2 R）通过非经典机制调节基底外侧膜递送;（ii）分选连接蛋白9（SNX 9）区分Smad 3依赖性反应和Smad 2;（iii）ErbB家族成员的诱导对TGF-β调节的间充质细胞表型至关重要。在这个竞争性的更新中，我们将使用各种生物化学，生物学和形态学方法来扩展这些概念。首先，我们将确定哺乳动物retromer复杂的调节TGF-？非法交易。由于许多疾病是由于蛋白质分选或转运至特定细胞区域的能力缺陷所致，因此描述有效反式作用因子提供了改变细胞对TGF-β反应的潜在机制。其次，SNX 9控制Smad 3转录活性的机制将被表征。鉴于大多数Smad依赖性转录是通过Smad 3介导的，这些研究提出了可以开发干预策略以增强或减弱Smad 3特异性反应的可能性。第三，EGF家族成员在促纤维化TGF-？将定义信令。自从TGF-？是由直接和间接介质的协同作用，我们的研究发现，ErbB配体是基本的促纤维化表型后看到的TGF-？为组织纤维化的发生提供了新的范例