Mayo Clinic Center for Clinical Proteomics

梅奥诊所临床蛋白质组学中心

• 批准号: 10632009
• 负责人: Rafael Fonseca
• 金额: $ 110.19万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 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/10632009
• 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; Dedications; 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; 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; Research; Research Personnel; Resistance; Resolution; Sampling; Scientist; Technology; Thalidomide; Universities; Visualization; anti-cancer; arm; assay development; biomarker identification; candidate validation; clinical assay development; clinical center; clinical translation; comparative genomic hybridization; data handling; design; detection sensitivity; exome sequencing; experience; experimental study; forging; genetically modified cells; genomic aberrations; humanized mouse; immune modulating agents; 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; technology platform; transcription factor; transcriptome; transcriptome sequencing; transcriptomics; treatment response; tumor; ubiquitin-protein ligase

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.

项目总结/摘要 我们建议建立一个多学科的马约临床蛋白质组学中心，其总体目标是 鉴定和验证多发性骨髓瘤治疗反应的蛋白质组学生物标志物。这个中心是一个 一个独特的联盟，由马约诊所的两个团队和杨百翰医院的一个团队组成 大学这个由马约诊所的医生和科学家组成的团队在多发性骨髓瘤方面具有专长， 诊断、治疗、临床试验和基础研究以及大规模 光谱学、基因组学、转录组学、生物信息学和临床分析开发将加入 由杨百翰大学的新型仪器/平台开发方面的世界专家创建， 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。一个最近 已开发的称为免疫调节酰亚胺药物（IMiD）的一类药物已经成为免疫调节的主要药物。 多发性骨髓瘤的治疗，虽然复发的患者是高，主要是由于耐药性。的 IMiDs的主要靶点是cereblon（CRBN），这是其抗癌和免疫活性所必需的。 IMiD激活CRBN E3泛素连接酶复合物的酶活性，导致泛素化， 降解转录因子IKZF 1和IKZF 3，从而调节肿瘤存活和免疫应答 通过下调IRF 4和MYC。对于临床前研究，我们的跨学科团队将承担 发现研究涉及全面的蛋白质基因组学表征（蛋白质组，磷酸化蛋白质组， 泛素化组、基因组、转录组）的细胞模型（基因工程细胞系、人源化细胞系、人源化 小鼠模型和患者样品）以鉴定IMiD抗性的分子标记物。鉴于其中心地位， CRBN介导的IMiD耐药途径，我们将通过以下方式启动我们的靶向蛋白质组学工作： 致力于开发CRBN及其下游效应物的靶向检测方法。同时，我们预计 通过我们的发现研究确定其他候选蛋白质，针对这些蛋白质的靶向测定也将被 开发最后，该提案的共同研究者Vincent Rajkumar博士将提供来自 三项NCI申办的临床试验，专门用于观察IMiD的效果， 通过有针对性的方法。通过整合多种技术的不断发展， 在包括CyTOF在内的平台上，我们将确保在提案期间保持敏捷性。 凭借成熟的先进基础设施，在CAP/CLIA检测开发方面经验丰富的人员， 专用仪器、高分析能力和现有的QC、数据处理和 生物信息学，拟议中的马约临床蛋白质组学中心准备成功地发现和 验证多发性骨髓瘤中IMiD耐药的蛋白质组学标志物。

项目成果

sBioSITe enables sensitive identification of the cell surface proteome through direct enrichment of biotinylated peptides.

• DOI: 10.1186/s12014-023-09445-6
• 发表时间: 2023-12-05
• 期刊: CLINICAL PROTEOMICS
• 影响因子: 3.8
• 作者: Garapati, Kishore;Ding, Husheng;Charlesworth, M. Cristine;Kim, Yohan;Zenka, Roman;Saraswat, Mayank;Mun, Dong-Gi;Chavan, Sandip;Shingade, Ashish;Lucien, Fabrice;Zhong, Jun;Kandasamy, Richard K.;Pandey, Akhilesh
• 通讯作者: Pandey, Akhilesh