Harnessing receptor pleiotropy to control cancer

利用受体多效性来控制癌症

• 批准号: 9304532
• 负责人: Daryl Ewald Klein
• 金额: $ 14.34万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-06 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9304532
• 关键词: Affect; Affinity; Area; Automobile Driving; Biology; Biophysics; Bypass; Cancer Control; Cells; Clinical; Clinical Trials; Development; Dimerization; Disease; Disease Progression; Disease model; Embryonic Development; Functional disorder; Goals; Growth; Growth Factor; Growth and Development function; Hybrids; Immune Evasion; Interferometry; Investigation; Kinetics; Knowledge; Length; Ligands; Logic; Malignant - descriptor; Malignant Neoplasms; Medicine; Membrane; Molecular; Monitor; Monoclonal Antibodies; Mutation; Nature; Neoplasm Metastasis; Oncogenic; Outcome; Output; Patients; Perception; Pharmaceutical Preparations; Phenotype; Process; Property; Protein Engineering; Protein Kinase; Proteins; Receptor Activation; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Recruitment Activity; Research; Research Proposals; Resistance; Resolution; Signal Pathway; Signal Transduction; Solid Neoplasm; System; Techniques; Technology; Therapeutic; Time; Tissues; Up-Regulation; Work; cancer cell; clinically significant; collaborative approach; cytokine; design; digital; dimer; extracellular; high throughput screening; immunological synapse; inhibitor/antagonist; insight; interdisciplinary approach; kinase inhibitor; malignant phenotype; mutant; novel strategies; pleiotropism; pressure; prevent; receptor; resistance mechanism; response; small molecule; success; tumor; tumorigenesis

Project summary / abstract: The goal of this proposal is to understand the mechanisms of differential signaling among receptors important for the development of cancer, and to use this knowledge to design strategies to suppress malignant disease. Cancers often highjack the signaling logic of embryonic development for growth and metastasis and bypass natural regulatory controls. This allows receptors on cancer cells to remain in a perpetual “on-state”. Current therapeutic approaches therefore attempt to prevent receptor activation by promoting non-signaling competent receptor “off-states”. This, however, produces an enormous selective pressure that drives the rapid outgrowth of resistance. Recent findings suggest that receptors important for oncogenesis actually allow for diverse signaling outputs rather than just discrete on/off states – functioning more like a rheostat than a digital convertor. This newly discovered property opens the possibility of actively `tuning' tumor signaling away from metastasis. This proposal investigates the mechanisms that control receptor signal bias in developmental and disease models using an array of techniques that span the relevant length and time scales necessary to reveal receptor and cellular signaling dynamics. My approach incorporates cutting-edge biophysical technologies (including cryo-EM and interferometry) that will help decipher the `logic' governing signal bias among oncogenic receptors. A quantitative and high-resolution view of the differential signaling process will provide important fundamental insight into cancer receptor biology and should open new avenues for the design of modulatory therapeutics that limit disease progression.

项目摘要/摘要： 这项建议的目标是了解受体之间差异信号的机制 为了癌症的发展，并利用这一知识来设计抑制恶性疾病的策略。 癌症经常劫持胚胎发育的信号逻辑，以促进生长和转移并绕过 自然的监管控制。这使得癌细胞上的受体能够保持永久的“开启状态”。当前 因此，治疗方法试图通过促进非信号活性来防止受体激活 受体“关闭状态”。然而，这产生了巨大的选择压力，推动了快速的增长。 抵抗的力量。最近的发现表明，对于肿瘤发生很重要的受体实际上允许不同的 信号输出，而不仅仅是离散的开/关状态-功能更像变阻器而不是数字 转换器。这一新发现的特性使人们有可能主动地将肿瘤信号调谐到 转移。这项建议调查了在发育和发育过程中控制受体信号偏差的机制。 使用一系列技术的疾病模型，这些技术跨越相关的长度和时间尺度来揭示 受体和细胞信号动力学。我的方法结合了尖端的生物物理技术 (包括低温电磁法和干涉测量法)，这将有助于破译支配信号偏差的 致癌受体。差异信号传递过程的定量和高分辨率视图将提供 对癌症受体生物学的重要基础洞察力，并应为设计 限制疾病进展的调节疗法。