A chemical biology approach towards understanding the anti-cancer innate immunity

了解抗癌先天免疫的化学生物学方法

基本信息

批准号：
9123710
负责人：
Lingyin Li
金额：
$ 24.9万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-04 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9123710
关键词：
Accounting Adjuvant Affect Agonist Antineoplastic Agents Binding Biochemical Biochemistry Biological Assay Biological Factors Biology Biomedical Research Blood Blood Cells Cancer Vaccines Candidate Disease Gene Cell Line Cell surface Cells Chemicals Chemistry Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Cytoplasm DNA Data Degradation Pathway Development Dimethylxanthenone Acetic Acid Dinucleoside Phosphates Doctor of Philosophy Dose Drug Formulations Drug Kinetics Drug Targeting Engineering Enzymes Flow Cytometry Genes Genetic Genetic Screening Goals Growth Haploidy Health Human Hydrolase Imiquimod Immune Immune response Immune system Immunity Immunology Insertional Mutagenesis Interferon Activation Interferons Kinetics Lead Learning Ligands Malignant Neoplasms Malignant neoplasm of urinary bladder Measures Mediating Membrane Membrane Transport Proteins Modeling Molecular Target Mus Natural Immunity Organic Chemistry Paracrine Communication Pathway Analysis Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phase Philosophy Phosphotransferases Plasma Postdoctoral Fellow Quality of life Reaction Receptor Signaling Route Signal Transduction Skin Cancer Solid Neoplasm Specificity Structure Surface TNFRSF5 gene Testing Therapeutic Therapeutic Intervention Training Universities Wisconsin Work analog base cancer cell cancer pharmacology cancer therapy chemical genetics cyclic compound design drug candidate drug development drug testing experience extracellular genetic approach improved insight interest leukemia man medical schools mouse model next generation sequencing novel phosphoric diester hydrolase professor receptor response stem cell fate synthetic drug tool transcription factor tumor uptake

项目摘要

DESCRIPTION (provided by applicant): Dr. Lingyin Li was trained in chemical biology and biochemistry. Her graduate training was with Professor Laura Kiessling at University of Wisconsin-Madison, where she used chemistry/engineering strategies to control stem cell fate and she received a Ph. D in organic chemistry. Hoping to learn what the most important problems are in biomedical research, she is seeking her postdoc training with Professor Timothy Mitchison at Harvard Medical School. With her experience there in cancer pharmacology, Dr. Li's long-term goal is to lead her academic team to make an impact on cancer treatment and significantly improve patients' quality of life. Using reverse pharmacology, Dr. Li recently identified the molecular target of a drug called DMXAA that cured solid tumors in mice via activating innate immunity, but failed in phase III human clinical trials. She discovered that DMXAA functions as an agonist ligand for mouse, but not human STING (Stimulator of the Interferon Genes), explaining its activity in mouse and lack of efficacy in man. STING is the receptor for the newly- discovered 2nd messenger 2'3'-cGAMP, which is synthesized by cGAS in response to DNA in the cytoplasm. 2'3'-cGAMP binds to STING, activates TBK-1 (a kinase) and IRF-3 (a transcription factor), and induces a panel of host response genes including interferon α/ß. This pathway opens multiple possible routes to therapeutic intervention. In this proposed project, Dr. Li will seek to uncover biochemical mechanisms in the cGAMP- STING pathway and in parallel develop therapeutic hypotheses and lead compounds. She proposes to use 2'3'-cGAMP analogs that she has synthesized to target human STING and her preliminary results showed extracellular activity of these analogs. She has also discovered the dominant hydrolase for 2'3'-cGAMP, which turned out to be an extracellular enzyme. These results hint extracellular biology of 2'3'-cGAMP, which is not being pursued by the immunology field, and might allow rapid drug development. In her aim 1, Dr. Li plans to further characterize her analogs and test them in mouse tumor models, which is her first bold move towards making an impact on cancer therapy. In aim 2, Dr. Li will study the degradation mechanisms of 2'3'-cGAMP and its internalization kinetics. The results will suggest whether there exists a cell surface signaling receptor for 2'3'-cGAMP or a membrane transporter that eventually leads to intracellular 2'3'-cGAMP signaling. In Aim 3, Dr. Li will use a genetics screen to identify signalig components for extracellular 2'3'-cGAMP (e.g. a membrane receptor or transporter) and this will lead to new biology and novel drug targets. Activating the innate immune system to stop nurturing cancer cells and instead attack them has already shown high potential as a therapeutic philosophy. Dr. Li's chemical genetics approach will provide more tools to awaken our anti- cancer immunity.

描述（由申请人提供）：Lingyin Li 博士接受过化学生物学和生物化学方面的培训，她的研究生培训是在威斯康星大学麦迪逊分校的 Laura Kiessling 教授的指导下进行的，在那里她使用化学/工程策略来控制干细胞的命运，并获得了有机化学博士。希望了解生物医学研究中最重要的问题，她正在哈佛医学院的蒂莫西·米奇森教授那里寻求博士后培训，凭借她在癌症药理学方面的经验。李博士的长期目标是带领她的学术团队对癌症治疗产生影响并显着改善患者的生活质量，李博士最近利用反向药理学确定了一种名为 DMXAA 的药物的分子靶点，该药物可以治愈小鼠实体瘤。她发现 DMXAA 可以作为小鼠的激动剂配体，但不能作为人类 STING（干扰素基因刺激剂）的配体，这解释了它在小鼠中的活性以及在小鼠中缺乏功效。 STING 是新发现的第二信使 2'3'-cGAMP 的受体，它是由 cGAS 响应细胞质中的 DNA 合成的，与 STING 结合，激活 TBK-1（一种激酶）。）和IRF-3（转录因子），并诱导一系列宿主反应基因，包括干扰素α/β。在这个拟议的项目中，李博士将寻求多种可能的治疗干预途径。她建议使用她合成的 2'3'-cGAMP 类似物来靶向人类 STING，并且她的初步结果显示了这些类似物的细胞外活性。她还发现了 2'3'-cGAMP 的主要水解酶，结果证明它是一种细胞外酶。这些结果暗示了 2'3'-cGAMP 的细胞外生物学，但该酶并未被研究人员所追寻。在她的目标 1 中，李博士计划进一步表征她的类似物并在小鼠肿瘤模型中测试它们，这是她在目标 2 中迈向影响癌症治疗的第一个大胆举措。李博士将研究2'3'-cGAMP的降解机制及其内化动力学，结果将表明是否存在2'3'-cGAMP的细胞表面信号受体或最终导致细胞内的膜转运蛋白。 2'3'-cGAMP 信号传导。在目标 3 中，李博士将使用遗传学筛选来识别细胞外 2'3'-cGAMP 的信号成分（例如膜受体或转运蛋白），这将带来新的生物学和新药物。激活先天免疫系统以停止培育癌细胞并攻击它们，作为一种治疗理念，李博士的化学遗传学方法已显示出巨大的潜力，将为唤醒我们的抗癌免疫力提供更多工具。