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）：拟议的研究基于以下假设：抑制转化生长因子β（TGFBETA）信号转导途径可以在某些癌症中提供有效而特定的干预措施。 TGFBETA与各种各样的人类疾病有关，包括癌症，免疫调节，伤口愈合和组织修复。在癌症中，TGFBETA促进了肿瘤细胞的进展和扩散。肿瘤来源的TGFBETA可以通过直接作用，通过对癌细胞的直接作用，通过局部或全身免疫抑制来帮助肿瘤性，并通过改变促进侵入性的基质组织的改变。提出了一种化学遗传学方法来产生和表征干预TGFBETA信号传导的肽适体。工作假设是，可以通过了解磷酸化的SMAD SMAD（SMAD-P）复合物与其他蛋白质的特定相互作用来实现TGFBETA反应的选择性扰动，并且可以通过干预特定的SMAD-P相互作用子集来干预选择性干预策略。具体目的包括使用十五个已知的SMAD相互作用图案来产生肽适时，这些肽适中，这些肽对TGFBETA信号转导的特定反应，适体的溶液结合特性的表征，结构功能分析，通过定向和随机诱变和在细胞中的随机诱变和对媒体的效果的作用，以评估其对媒体的影响。拟议的研究将提供新的策略和试剂，以驱动介导的信号通路，以识别在特定病理状态中可能很重要的目标相互作用，并确定对SMAD-P的良好配体的结构。