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Harnessing receptor pleiotropy to control cancer

利用受体多效性来控制癌症

基本信息

批准号：
9751075
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
项目类别：
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/9751075
关键词：
Affect Affinity Area Automobile Driving Biology Biophysics Bypass Cancer Control Cells Clinical Clinical Trials Cryoelectron Microscopy Development 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 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 developmental disease digital dimer extracellular high throughput screening immunological synapse inhibitor/antagonist insight interdisciplinary approach kinase inhibitor malignant phenotype mutant novel strategies pleiotropism pressure prevent receptor recruit resistance mechanism response small molecule success tumor tumorigenesis

项目摘要

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：