Functional Genomics Approach to the Role of the JAK/STAT and MAPK Pathway in CBD

功能基因组学方法研究 JAK/STAT 和 MAPK 通路在 CBD 中的作用

• 批准号: 8520310
• 负责人: Li Li
• 金额: $ 12.52万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-21 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8520310
• 关键词: Acute Myelocytic Leukemia; Affect; Antigen Presentation; Antigen-Presenting Cells; Appointment; Area; Beryllium; Bioinformatics; Biological Assay; Biological Markers; Biometry; Biopsy; Blood Cells; Blood Tests; CD4 Positive T Lymphocytes; Candidate Disease Gene; Cell Proliferation; Cells; Chronic; Chronic berylliosis; Chronic lung disease; Clinic; Clinical; Colorado; Critical Care; Cytokine Network Pathway; Data; Dendritic cell activation; Dermatology; Development; Diagnostic; Disease; Doctor of Medicine; Doctor of Philosophy; Ecology; Education; Environment; Environmental Health; Exposure to; Faculty; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Predisposition to Disease; Genomics; Germany; Goals; Grant; Granuloma; Granulomatous; Head; Health; Health Sciences; Human; Hypersensitivity; Immune; Immune System Diseases; Immune response; Immunotherapeutic agent; In Vitro; Inflammation; Janus kinase; K-Series Research Career Programs; Laboratories; Lead; Light; Lung; Lung diseases; Lymphocyte; Measurement; Mediating; Medicine; Mentors; Microarray Analysis; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Profiling; Names; Natural Immunity; Nature; Occupational Health; Pathogenesis; Pathway interactions; Patients; Peripheral; Population; Predisposition; Preparation; Prevalence; Process; Production; Proteins; Publications; Regulation; Research; Research Personnel; Research Proposals; Reverse Transcriptase Polymerase Chain Reaction; Role; SECTM1 gene; STAT protein; Salts; Science; Science of genetics; Scientist; Small Interfering RNA; System; Systems Analysis; T memory cell; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Technology; Testing; Th1 Cells; Therapeutic; Tissue-Specific Gene Expression; Training; Universities; Up-Regulation; Update; Viral Tumor Antigens; Workplace; base; clinical Diagnosis; cytokine; experience; follower of religion Jewish; functional genomics; immune function; immunological synapse; improved; innovation; insight; instructor; knock-down; lymphocyte proliferation; medical schools; novel; outcome forecast; post-doctoral training; programs; public health relevance; research study; skills; transcription factor

DESCRIPTION (provided by applicant) This proposal outlines a comprehensive three year training plan for the candidate to become an independent scientist in academic pulmonary and critical care medicine. The candidate earned her Ph.D. from the Tongji Medical College, Huazhong University of Science &Technology (HUST) and M.D. from University of Ulm, Germany. Her research focused on the development of novel immunotherapeutic strategies for patients with acute myeloid leukemia (AML). She subsequently received postdoctoral training in the Department of Dermatology, University of Colorado Denver (UCD). Her research was highly focused on the cell-cell immunological synapse interactions between activated memory T lymphocytes and antigen presenting cells. In addition, she received his first academic appointment at National Jewish Health (NJH) in the Division of Environmental & Occupational Health Sciences (DEOHS) in the Department of Medicine studying the granulomatous lung disease chronic beryllium disease (CBD), which results from exposure to beryllium. Soon after her appointment, she was successful in obtaining a career development award from an institutional K12 through the Pulmonary Division, UCD. This grant provided her with a faculty appointment at an Instructor level at UCD. There, she developed proficiency in genomics, and the immunopathogenic mechanisms of CBD. With Dr. Maier, an expert in environmental sciences, genetics, genomics and bioinformatics, head of DEOHS, serving as the primary mentor, this program provides the candidate additional training in three essential areas: 1) education in genetics, genomics, biostatistics and updates in essential laboratory skills; 2) supervised preparation of research publications; 3) mentored development of her independent research proposal. Additional mentoring is provided by co-mentor Dr. Day, Ph.D., an expert in pulmonary innate immunity and inflammation with extensive prior mentoring experience, and an expert panel of scientists. This program will take place at UCD and NJH, both of which provide outstanding environment for training scientists. It offers state-of-the-art research and clinical facilities, outstanding opportunities for education and the exchange of scientific ideas, and strong commitment to the candidate's development as an independent investigator. The scientific proposal explores the novel hypothesis that patients with CBD have differential regulation of immune-related genes that ultimately leads to abnormalities in immune function and heightened susceptibility to be. Specifically, the central hypothesis is that Be-exposure results in the inappropriate activation of the JAK/STAT pathway and MAPK pathway and contributes to CBD pathogenesis. Therefore, the goal of this study is to gain insight into the mechanisms and pathogenic pathways important in CBD by conducting an in- depth analysis of the differentially expressed candidate genes in CBD. Its specific aims are: 1) To demonstrate that the JAK/STAT pathway and MAPK pathway related genes are inappropriately activated in CBD compared to BeS and Be-exposed controls with beryllium-exposure, validating these potentially important CBD candidate gene identified in the microarray analysis using qRT-PCR. 2) To functionally assess the role of the candidate genes in the JAK/STAT pathway and MAPK pathway in CBD pathogenesis by assessing either the over- expression of the gene product using the Flp-in expression analysis system in vitro, or the reduction of the gene product using siRNA "knock down" analysis. 3) To investigate whether the differentially genes are associated with CBD (n=100) and BeS (n=100) in a larger separate population and thus reveal potential novel biomarkers for CBD. Insights garnered from these data will significantly add to the understanding of molecular mechanisms of CDB and may lead to development of potential novel biomarker and new targets for study as potential therapeutic approaches for CBD. Public Health Relevance: Exciting preliminary studies show that the peripheral blood cells from CBD and BeS demonstrate differential gene expression profiles relevant to the immune function and pathogenesis of these processes, compared to Be-exposed non-diseased controls. This proposal is to gain insight into the mechanisms and pathogenic pathways important in CBD by conducting an in-depth analysis of the differentially expressed candidate genes in CBD focusing on a pathway that is to a Th1 immune response. The results may improve our understanding of factors involved in the development of CBD, aspects which determine prognosis, and targets for therapy, serves as a model of exposure-related immunologic disease with potential application to other environmentally induced diseases.

描述（由申请人提供） 该提案概述了一项全面的三年培训计划，使候选人成为学术肺和重症监护医学的独立科学家。候选人获得了博士学位。来自汤吉医学院，瓦兹港科学技术大学（HUST）和德国乌尔姆大学的医学博士学位。她的研究重点是针对急性髓样白血病（AML）患者的新型免疫治疗策略的发展。随后，她接受了科罗拉多大学丹佛分校皮肤科（UCD）皮肤科的博士后培训。她的研究高度关注活化记忆T淋巴细胞和抗原呈递细胞之间的细胞免疫突触相互作用。此外，她在研究肉芽肿性肺部疾病慢性铍病（CBD）的医学系环境与职业健康科学（DEOHS）的国家犹太健康（NJH）中获得了他的第一个学术任命，这是由于暴露于孢子菌的暴露而导致的。约会后不久，她成功地通过UCD肺部从机构K12获得了职业发展奖。这笔赠款为她提供了UCD的教师任命。在那里，她发展了基因组学和CBD的免疫发病机制的熟练程度。 与Deohs负责人的环境科学，遗传学，基因组学和生物信息学专家Maier博士一起，该计划为候选人提供了三个基本领域的候选培训：1）遗传学，基因组学，生物统计学和更新的教育 基本的实验室技能； 2）监督研究出版物的准备； 3）指导她的独立研究建议的发展。 Co-Enctor Day博士博士提供了额外的指导，Day博士是肺部先天免疫和炎症专家，并具有丰富的先前指导经验，也是科学家的专家小组。 该计划将在UCD和NJH举行，两者都为培训科学家提供了杰出的环境。它提供了最先进的研究和临床设施，教育的出色机会和科学思想的交流以及对候选人作为独立研究者的发展的坚定承诺。 该科学提案探讨了以下新假设：CBD患者对免疫相关基因的调节差异，该基因最终导致免疫功能异常并提高了易感性。具体而言，中心假设是暴露会导致JAK/STAT途径和MAPK途径的不适当激活，并有助于CBD发病机理。因此，这项研究的目的是通过对CBD中差异表达的候选基因进行深入分析，深入了解CBD中重要的机制和致病途径。 它的具体目的是：1）证明与BES和暴露于铍暴露的BES和暴露对照相比，CBD中的JAK/STAT途径和MAPK途径相关的基因被不适当地激活，从而验证了使用QRT-PCR在微阵列分析中鉴定出的这些潜在重要的CBD候选基因。 2）通过使用FLP-IN表达分析系统在体外评估基因产物的过度表达，或使用siRNA使用siRNA“敲除”分析来评估候选基因在JAK/STAT途径和MAPK途径中的作用。 3）研究差异基因是否与较大的单独种群中的CBD（n = 100）和BES（n = 100）相关，从而揭示了CBD的潜在新型生物标志物。从这些数据中获得的洞察力将显着增加对CDB分子机制的理解，并可能导致潜在的新型生物标志物的发展，并作为CBD的潜在治疗方法进行研究。 公共卫生相关性：令人兴奋的初步研究表明，与暴露于暴露于未探测的对照相比，CBD和BES的外周血细胞和BES表现出与这些过程的免疫功能和发病机理相关的差异基因表达谱。该建议是通过对CBD中差异表达的候选基因进行深入分析，以深入了解CBD中重要的机制和致病途径，该基因的重点是针对Th1免疫反应的途径。结果可以提高我们对CBD发展的因素的理解，确定预后的方面和治疗靶标，是暴露相关免疫疾病的模型，并可能应用于其他环境诱发的疾病。

项目成果

Genomic biomarkers in chronic beryllium disease and sarcoidosis.

• DOI: 10.1016/j.rmed.2021.106390
• 发表时间: 2021-10
• 期刊: Respiratory medicine
• 影响因子: 4.3
• 作者: Lin NW;Maier LA;Mroz MM;Jacobson S;MacPhail K;Liu S;Lei Z;Barkes BQ;Fingerlin TE;Hamzeh N;Mayer AS;Restrepo CI;Chhabra D;Yang IV;Li L
• 通讯作者: Li L