Platform for Structure-Function Studies of Adhesion GPCRs implicated in Cancer

与癌症相关的粘附 GPCR 的结构功能研究平台

• 批准号: 8926375
• 负责人: RAYMOND C STEVENS
• 金额: $ 17.94万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8926375
• 关键词: Address; Adhesions; Antibodies; Baculovirus Expression System; Biochemical; Biological Assay; Biological Markers; Biology; Breast; CD97 gene; Cell Communication; Cell secretion; Cells; Chimeric Proteins; Colorectal Cancer; Complex; Crystallization; Data; Development; Differentiation and Growth; Epidermal Growth Factor Receptor; Esophageal; Exploratory/Developmental Grant; Family; Funding; G-Protein-Coupled Receptors; Generations; Goals; Health; Human; Immune response; Inflammatory Response; Knowledge; Length; Ligands; Malignant Neoplasms; Membrane; Metabolism; Modeling; Molecular; Molecular Conformation; N-terminal; Outcome; Outcome Study; Pancreas; Pharmaceutical Preparations; Phase; Physiological Processes; Preparation; Process; Production; Proteins; Publishing; Resources; Role; Sampling; Scaffolding Protein; Shapes; Signal Transduction; Stomach; Structure; Therapeutic; Thyroid Gland; Tumor Suppressor Proteins; adhesion receptor; base; cancer type; design; drug development; drug market; large scale production; member; migration; mimetics; nanodisk; neurotransmission; novel; particle; receptor; reconstitution; scaffold; small molecule; success; therapeutic target; tool; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): The project "Platform for Structure-Function Studies of Adhesion GPCRs implicated in Cancer" focuses on establishing the essential basis for studying adhesion GPCRs, which are the second largest family of G-protein coupled receptors (GPCRs). These receptors regulate the migration and development of cells by controlling cell-cell interactions, as well as the intracellular signaling, which makes them of utmost importance because of their roles in tumorigenesis and cancer progression. Their importance, as novel cancer therapeutic targets, is well documented and they are considered biomarkers for specific types of cancers. However, adhesion GPCRs are also the least understood GPCR family. Structural and functional/biochemical studies have been limited or almost non-existent due to difficulties in producing purified samples. Structural information of proteins is a powerful resource for understanding their molecular activities and mechanisms of function, as well as for designing specific therapeutics making them key tools for drug development. Here, we propose to initiate the road to structural determination for members of adhesion GPCRs, by focusing on one member, CD97 receptor. CD97 is a member of the epidermal growth factor (EGF) receptor family involved in progression of thyroid, breast, gastric, esophageal, pancreatic, colorectal cancers, etc. and thus has been suggested as a direct tumor suppressor target. We aim to establish the basis for large-scale production of stabilized CD97 constructs for crystallization and biochemical characterization, which include the use of antibodies. The outcome of the proposed study will: 1) provide quantities of CD97 for functional studies, 2) enable the determination of the structure of the first adhesion GPCR, and 3) provide a platform for further studies of the entire adhesion GPCR family. Thus, this study will set the essentials for more comprehensive studies of adhesion GPCRs towards understanding how they regulate cancer development and progression and provide a basis for designing new drugs.

描述（由申请人提供）：“与癌症有关的粘附GPCR结构功能研究平台”项目重点是建立研究粘附GPCR的必要基础，粘附GPCR是G蛋白偶联受体（GPCR）的第二大家族。这些受体通过控制细胞间相互作用以及细胞内信号传导来调节细胞的迁移和发育，这使得它们因其在肿瘤发生和癌症进展中的作用而变得至关重要。它们作为新型癌症治疗靶点的重要性已得到充分证明，并且被认为是特定类型癌症的生物标志物。然而，粘附 GPCR 也是人们最不了解的 GPCR 家族。由于生产纯化样品的困难，结构和功能/生化研究受到限制或几乎不存在。蛋白质的结构信息是了解其分子活性和功能机制以及设计特定疗法的强大资源，使其成为药物开发的关键工具。在这里，我们建议通过关注其中一个成员 CD97 受体，开启粘附 GPCR 成员结构测定的道路。 CD97 是表皮生长因子 (EGF) 受体家族的成员，参与甲状腺癌、乳腺癌、胃癌、食道癌、胰腺癌、结直肠癌等的进展，因此被认为是直接的肿瘤抑制靶标。我们的目标是为大规模生产用于结晶和生化表征（包括抗体的使用）的稳定 CD97 构建体奠定基础。拟议研究的结果将：1）为功能研究提供大量 CD97，2）能够确定第一个粘附 GPCR 的结构，3）为整个粘附 GPCR 家族的进一步研究提供平台。因此，这项研究将为更全面地研究粘附 GPCR 奠定基础，以了解它们如何调节癌症的发生和进展，并为设计新药提供基础。