Mayo Clinic Center for Clinical Proteomics

梅奥诊所临床蛋白质组学中心

基本信息

批准号：
10459980
负责人：
Rafael Fonseca
金额：
$ 114.06万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10459980
关键词：
Basic Science Bioinformatics Biological Assay Biological Markers Cell Line Cells Clinic Clinical Chemistry Clinical Research Clinical Trials Complex Conduct Clinical Trials Cost Analysis Cytogenetics Cytometry Data Data Analyses Databases Detection Development Diagnosis Discipline Disease Down-Regulation Drug resistance Ensure Gene Expression Generations Genetic Engineering Genome Genomics Goals Human Human Resources IRF4 gene Imides Immune Immune response Immunomodulators Infrastructure Maps Mass Spectrum Analysis Mediating Modeling Molecular Target Multiple Myeloma Mutation Partner in relationship Pathway interactions Patients Peptides Pharmaceutical Preparations Phosphorylation Phosphotyrosine Physicians Post-Translational Protein Processing Protein Analysis Proteins Proteome Proteomics Publications Quality Control Regimen Relapse Research Research Personnel Resistance Resolution Sampling Scientist Technology Thalidomide Universities Visualization anti-cancer arm assay development base candidate validation clinical assay development clinical center clinical translation comparative genomic hybridization data handling design detection sensitivity exome sequencing experience experimental study genetically modified cells genomic aberrations humanized mouse immunoregulation improved innovation instrument instrumentation lenalidomide mass spectrometer molecular marker mouse model multidisciplinary multiple omics novel novel therapeutics phosphoproteomics pomalidomide pre-clinical pre-clinical research predicting response protein biomarkers protein expression proteogenomics reference genome response success targeted sequencing transcription factor transcriptome transcriptome sequencing transcriptomics treatment research treatment response tumor ubiquitin-protein ligase

项目摘要

PROJECT SUMMARY/ABSTRACT We propose to create a multidisciplinary Mayo Clinic Center for Clinical Proteomics with the overarching goal of identifying and validating proteomic biomarkers for treatment response in multiple myeloma. This center is a unique alliance comprising of two teams within the Mayo Clinic umbrella and one team at Brigham Young University. This team of physicians and scientists at Mayo Clinic with expertise in multiple myeloma diagnosis, treatment, clinical trials and basic research as well as technologies such as mass spectrometry, genomics, transcriptomics, bioinformatics and clinical assay development will be joined by a world expert in novel instrument/platform development at Brigham Young University to create a unique center. Multiple myeloma is a complex disease with several distinct cytogenetic subtypes. A recently developed class of drugs designated immunomodulatory imide drugs (IMiDs) has become a mainstay of treatment of multiple myeloma although relapses among patients is high mainly due to drug resistance. The primary target of IMiDs is cereblon (CRBN), which is absolutely required for its anti-cancer and immune activity. IMiDs activate the enzymatic activity of the CRBN E3 ubiquitin ligase complex leading to ubiquitylation and degradation of transcription factors IKZF1 and IKZF3, thereby regulating tumor survival and immune response through downregulation of IRF4 and MYC. For the preclinical arm, our interdisciplinary team will undertake discovery studies involving comprehensive proteogenomic characterization (proteome, phosphoproteome, ubiquitylome, genome, transcriptome) of multiple myeloma models (genetically engineered cell lines, humanized mouse models and patient samples) to identify molecular markers of IMiD resistance. Given the centrality of CRBN-mediated pathways in IMiD resistance, we will jumpstart our targeted proteomics efforts by focusing on developing targeted assays for CRBN and its downstream effectors. In parallel, we anticipate identifying additional candidate proteins through our discovery studies, for which targeted assays will also be developed. Finally, Dr. Vincent Rajkumar, a co-investigator on this proposal, will provide access to samples from three NCI-sponsored clinical trials specifically designed to look at effects of IMiDs enabling validation of candidates through a targeted approach. By incorporating continuous development of multiple technology platforms including CyTOF, we will ensure that we maintain agility over the duration of the proposal. With an established advanced infrastructure, personnel experienced in the development of CAP/CLIA assays, dedicated instrumentation, high analytical capacity and existing pipelines for QC, data handling and bioinformatics, the proposed Mayo Clinic Center for Clinical Proteomics is poised for success to discover and validate proteomic markers of IMiD resistance in multiple myeloma.

项目摘要/摘要我们建议创建一个具有总体目标的临床蛋白质组学临床蛋白质组学中心鉴定和验证蛋白质组学生物标志物在多发性骨髓瘤中的治疗反应。这个中心是一个独特的联盟由梅奥诊所雨伞内的两支球队和杨百翰的一支团队组成大学。 Mayo诊所的这支由多发性骨髓瘤专业知识的医师和科学家团队诊断，治疗，临床试验和基础研究以及质量等技术光谱，基因组学，转录组学，生物信息学和临床分析将连接由杨百翰大学的新型仪器/平台开发专家创建的专家独特的中心。多发性骨髓瘤是一种复杂的疾病，具有几种不同的细胞遗传学亚型。最近开发的指定免疫调节酰亚胺药物（IMIDS）的药物已成为多发性骨髓瘤的治疗尽管患者之间的复发很高，主要是由于耐药性。这 Imids的主要靶标是Cereblon（CRBN），其抗癌和免疫活性绝对需要。 IMIDS激活CRBN E3泛素连接酶复合酶的酶活性，导致泛素化和转录因子IKZF1和IKZF3的降解，从而调节肿瘤存活和免疫反应通过下调IRF4和MYC。对于临床前部门，我们的跨学科团队将进行涉及综合蛋白质组学特征的发现研究（蛋白质组，磷蛋白组，多个骨髓瘤模型的泛素体，基因组，转录组）（基因工程细胞系，人源化小鼠模型和患者样品）以鉴定iMID耐药性的分子标记。考虑到中心 CRBN介导的IMID抗性途径，我们将通过专注于开发CRBN及其下游效应子的目标测定法。同时，我们预计通过我们的发现研究确定其他候选蛋白质，针对目标的测定也将是发达。最后，该提案的共同研究员Vincent Rajkumar博士将提供对样品的访问三项专门设计的NCI赞助的临床试验，以查看IMID的影响，以实现验证通过针对性的方法候选人。通过结合多种技术的持续开发包括Cytof在内的平台，我们将确保在提案期间保持敏捷性。凭借建立的高级基础设施，在开发CAP/CLIA分析方面经历的人员， QC，数据处理和拟议的梅奥临床蛋白质组学临床中心生物信息学有望成功发现和验证多发性骨髓瘤中IMID抗性的蛋白质组学标记。