Chemical Genetics of TGF-Beta Signal Transduction

TGF-β信号转导的化学遗传学

• 批准号: 7101072
• 负责人: F. Michael Hoffmann
• 金额: $ 25.29万
• 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 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7101072
• 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（由申请人提供）：所提议的研究基于这样的假设：抑制转化生长因子β（TGFβ）信号转导途径可以对某些癌症提供有效且特异性的干预。 TGFbeta 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可以通过直接作用于癌细胞、诱导血管生成、局部或全身免疫抑制以及促进侵袭性的基质组织的改变来促进致瘤性。提出了一种化学遗传学方法来生成和表征干预 TGFbeta 信号传导的肽适体。工作假设是，选择性干扰 TGFbeta 反应可以通过了解磷酸化 Smad (Smad-P) 复合物与其他蛋白质的特定相互作用来实现，并且可以通过干扰 Smad-P 相互作用的特定子集来实现选择性干预策略。具体目标包括使用 15 个已知的 Smad 相互作用基序来生成扰乱对 TGFbeta 信号转导的特异性反应的肽适体、适体溶液结合特性的表征、通过定向和随机诱变进行结构功能分析以及适体在细胞评估其对介导基因表达的影响。拟议的研究将提供新的策略和试剂来扰乱介导的信号通路，识别在特定病理状态下可能重要的靶标相互作用，以及识别作为 Smad-P 良好配体的结构。