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Defining, studying, and targeting sulfated tyrosine residues of cell surface receptors for disease treatment

Defining, studying, and targeting sulfated tyrosine residues of cell surface receptors for disease treatment
定义、研究和靶向细胞表面受体的硫酸化酪氨酸残基用于疾病治疗
批准号:
10504069
负责人:
Jiantao Guo
金额:
$30.1万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
已结题
起止时间:
2022-09-01 至 2024-06-30

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中文摘要
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英文摘要
Project Summary Protein tyrosine O-sulfation (PTS) of cell surface receptors plays a crucial role in extracellular biomolecular interactions that dictate various cellular processes, including cell adhesion, leukocyte trafficking, hormone activities, and immune responses. Tyrosine-sulfated receptors also participate in the development of various human diseases. Accordingly, PTS could emerge as an important drug target for the treatment of human diseases. Despite substantial advances in our knowledge of PTS, our current understanding of its biological significance is still in its infancy. It is this knowledge gap we seek to fill. In one direction, we will conduct comprehensive and discovery-based sulfoproteomic studies, which will lay the foundation to unveil the entire human receptor sulfointeractome and to identify disease-related sulfoprotein-protein interactions. In the second direction, we seek to define the role of PTS in the function of chemokine receptors. Chemokine signaling is central to chronic inflammatory conditions and participates in the development of many human diseases. At their N-terminal region, chemokine receptors contain tyrosine residues that can be sulfated to different extent (designated as “PTS level”). Our hypothesis is that chemokine receptors (and possibly other cell surface receptors in general) can be sulfated to various PTS levels, which allows the receptors to bind different ligands and leads to altered downstream biological/pathological events. In addition to basic mechanistic studies, we also seek to explore and develop novel therapeutic agents targeting PTS of chemokine receptors, such as C-X-C chemokine receptor type 4 (CXCR4). CXCR4 plays important roles in both physiological and pathological conditions, and it represents a crucial target in drug development. Our proposed work will be enabled by three technological breakthroughs, including the engineering of sulfotyrosine-recognizing small protein scaffolds, the use of state-of-the-art mass spectrometry methods, and the development of genetic method to encode sulfotyrosine in mammalian cells. Overall, the successful completion of the proposed work is expected to yield comprehensive data on receptor sulfoproteome, to gain insights into PTS-associated cellular biology, and to produce novel therapeutic interventions of human diseases.
期刊论文(1)
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会议论文
Engineering of SH2 Domains for the Recognition of Protein Tyrosine O-Sulfation Sites.
用于识别蛋白质酪氨酸 O-硫酸化位点的 SH2 结构域工程。
DOI: 10.1007/978-1-0716-3393-9_16
发表时间: 2023
期刊: Methods in molecular biology (Clifton, N.J.)
影响因子: --
作者: [Waldrop,SeanPaul, Niu,Wei, Guo,Jiantao]
通讯作者: Guo,Jiantao
Developing synthetic chemical biology strategies for biochemical investigations and biomedical applications
  • 批准号:
    10623497
  • 项目类别:
  • 资助金额:
    $37.17万
  • 财政年份:
    2023
  • 负责人:
    Jiantao Guo
  • 依托单位:
Nebraska Center for Integrated Biomolecular Communication (CIBC)
  • 批准号:
    10488641
  • 项目类别:
  • 资助金额:
    $224.49万
  • 财政年份:
    2016
  • 负责人:
    Jiantao Guo
  • 依托单位:
海外基金