Establishing Function of Understudied PRKCQ Kinase in Cellular Regulation and Disease

建立正在研究的 PRKCQ 激酶在细胞调节和疾病中的功能

基本信息

批准号：
9813191
负责人：
ALEXANDRA C. NEWTON
金额：
$ 17万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-20 至 2021-08-19
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9813191
关键词：
Address Alleles Automobile Driving Binding Biochemical Bioinformatics Biological Process Biology Cancer cell line Carcinogens Cell Survival Cells Clinical Trials Degenerative Disorder Diglycerides Disease Docking Enzymes Family Family member Fluorescence Resonance Energy Transfer Functional disorder Gene Proteins Genes Goals Growth Isoenzymes Malignant Neoplasms Mining Modeling Molecular Mus Muscle Muscular Dystrophies Mutation Oncogenes Oncogenic Patient-Focused Outcomes Patients Phorbol Esters Phosphorylation Phosphotransferases Positioning Attribute Protein Family Protein Kinase C Protein Kinase C Inhibitor Public Health Recurrence Regulation Research Sampling Second Messenger Systems Signal Transduction Structure Therapeutic Thinking Tumor Suppressor Proteins Vision base cancer clinical trial cancer genome cancer therapy cell growth regulation cell transformation comparative experimental study genome editing in vivo inhibitor/antagonist leukemia loss of function member molecular modeling muscular dystrophy mouse model mutant protein activation protein kinase C kinase receptor sensor three dimensional cell culture tumor tumorigenesis

项目摘要

Summary/Abstract The overall vision of our research is to gain a comprehensive understanding of the molecular mechanisms driving the function of understudied kinase PRKCQ in order to effectively target it in disease. PRKCQ encodes the protein kinase C (PKC) isozyme PKCq. The PKC family has been intensely investigated in the context of cancer since the discovery in the early 1980s that it is a receptor for the tumor-promoting phorbol esters. This led to the dogma that activation of PKC by phorbol esters promotes carcinogen-induced tumorigenesis. Nonetheless, PKC has been an elusive chemotherapeutic target despite decades of research. We recently established that, contrary to conventional thinking, PKC generally functions as a tumor suppressor, not an oncogene, thus explaining why 30+ years of clinical trials with PKC inhibitors not only failed but, in some cases, worsened patient outcome. In this proposal, we aim to combine bioinformatics, computational, biochemical, and cellular approaches to rapidly understand the molecular details of PKCq and how disease-associated mutations impact function and biology. Uncovering the function of PKCq in oncogenic signaling will inform on how to appropriately target it in cancer therapies.

摘要/摘要我们研究的总体愿景是全面了解驱动正在研究的激酶 PRKCQ 功能的分子机制，以便有效地将其瞄准疾病。 PRKCQ 编码蛋白激酶 C (PKC) 同工酶 PKCq。 PKC家族自 20 世纪 80 年代初发现以来，人们对癌症进行了深入研究它是促进肿瘤的佛波酯的受体。这导致了激活的教条佛波酯对 PKC 的作用促进致癌物诱导的肿瘤发生。尽管如此，PKC 尽管经过了数十年的研究，但它仍然是一个难以捉摸的化疗靶点。我们最近成立了与传统想法相反，PKC 通常起到肿瘤抑制作用，而不是肿瘤抑制作用。癌基因，从而解释了为什么 30 多年的 PKC 抑制剂临床试验不仅失败了，而且，在某些情况下，患者的预后会恶化。在这个提案中，我们的目标是结合生物信息学，计算、生化和细胞方法可快速了解分子细节 PKCq 的作用以及疾病相关突变如何影响功能和生物学。揭开 PKCq 在致癌信号传导中的功能将指导如何在癌症中适当地靶向它疗法。