Chemical Genetics of TGF-Beta Signal Transduction

TGF-β信号转导的化学遗传学

• 批准号: 6929846
• 负责人: F. Michael Hoffmann
• 金额: $ 25.9万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6929846
• 关键词: DNA binding protein; biological signal transduction; biotechnology; chemical genetics; combinatorial chemistry; directed evolution; functional /structural genomics; genetic screening; neoplasm /cancer genetics; peptide library; protein binding; transforming growth factors

DESCRIPTION (provided by applicant): The proposed research is based on the hypothesis that inhibition of the transforming growth factor beta (TGFbeta) signal transduction pathway can provide efficacious and specific intervention in some cancers. TGFbeta has been implicated in a broad variety of human diseases including cancer, immunoregulation, wound healing and tissue repair. In cancer, TGFbeta facilitates the progression and spread of tumor cells. The tumor-derived TGFbeta can aid tumorigenicity by direct actions on the cancer cell, by induction of angiogenesis, by local or systemic immunosuppression, and by alterations of stromal tissue that facilitate invasiveness. A chemical genetics approach is proposed to generate and characterize peptide aptamers that intervene in TGFbeta signaling. The working hypothesis is that selective perturbation of TGFbeta responses may be achieved by understanding the specific interactions of phosphorylated Smad (Smad-P) complexes with other proteins and that selective intervention strategies are possible by interfering with a specific subset of Smad-P's interactions. The specific aims include the use of fifteen known Smad interaction motifs to generate peptide aptamers that perturb specific responses to TGFbeta signal transduction, characterization of the solution binding properties of the aptamers, structure-function analysis by directed and random mutagenesis and expression of the aptamers in cells to evaluate their effects on Mediated-mediated gene expression. The proposed research will provide new strategies and reagents for perturbing the Mediated signaling pathway, for identifying target interactions that may be important in specific pathological states, and for identifying structures that are good ligands for Smad-P.

描述(申请人提供)：建议的研究是基于这样一个假设，即抑制转化生长因子β信号转导通路可以为某些癌症提供有效和特定的干预。转化生长因子β与多种人类疾病有关，包括癌症、免疫调节、伤口愈合和组织修复。在癌症中，TGFbeta促进肿瘤细胞的进展和扩散。肿瘤来源的TGFbeta可以通过对癌细胞的直接作用、通过诱导血管生成、通过局部或全身免疫抑制以及通过促进侵袭性的间质组织的改变来帮助肿瘤的发生。提出了一种化学遗传学方法来产生和表征干预转化生长因子β信号转导的多肽适配子。工作假设是，通过了解磷酸化Smad(Smad-P)复合体与其他蛋白质的特定相互作用，可以实现对TGFbeta反应的选择性扰动，并且通过干扰Smad-P相互作用的特定子集，选择性干预策略是可能的。具体目标包括利用15个已知的Smad相互作用基序产生干扰TGFbeta信号转导的特异性反应的多肽适配子，鉴定适配子的溶液结合性质，通过定向和随机突变进行结构-功能分析，以及在细胞中表达适配子以评估它们对介导性基因表达的影响。拟议中的研究将提供新的策略和试剂来干扰介导的信号通路，识别在特定病理状态下可能重要的靶相互作用，并识别Smad-P的良好配体结构。