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: 8336834
• 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 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8336834
• 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） 该提案概述了一个全面的三年培训计划，使候选人成为学术肺部和重症监护医学的独立科学家。这位候选人获得了博士学位。同济医学院、华中科技大学医学博士。来自德国的乌尔姆大学。她的研究重点是为急性髓细胞白血病（AML）患者开发新的免疫策略。她随后在科罗拉多丹佛大学（UCD）皮肤科接受博士后培训。她的研究主要集中在激活的记忆T淋巴细胞和抗原呈递细胞之间的细胞-细胞免疫突触相互作用。此外，她收到了他的第一个学术任命在国家犹太健康（NJH）在环境与职业健康科学（DEOHS）在医学系研究肉芽肿性肺病慢性铍病（CBD），这是由于暴露于铍。在她被任命后不久，她成功地通过肺科，UCD从机构K12获得了职业发展奖。这笔补助金为她提供了在UCD讲师级别的教师任命。在那里，她熟练掌握了基因组学和CBD的免疫病理机制。 Maier博士是环境科学、遗传学、基因组学和生物信息学方面的专家，也是DEOHS的负责人，作为主要导师，该计划为候选人提供了三个重要领域的额外培训：1）遗传学、基因组学、生物统计学和生物信息学方面的教育。 基本的实验室技能; 2）监督研究出版物的准备; 3）指导她独立研究提案的发展。额外的指导是由共同导师戴博士，博士，他是肺部先天免疫和炎症方面的专家，具有丰富的指导经验，并拥有一个专家科学家小组。 该计划将在UCD和NJH进行，这两个都为培训科学家提供了出色的环境。它提供最先进的研究和临床设施，出色的教育和科学思想交流机会，并坚定地致力于候选人作为独立研究者的发展。 这项科学提案探索了一种新的假设，即CBD患者对免疫相关基因有不同的调节，最终导致免疫功能异常和易感性增加。具体来说，中心假设是Be暴露导致JAK/STAT途径和MAPK途径的不适当激活，并导致CBD发病机制。因此，本研究的目标是通过对CBD中差异表达的候选基因进行深入分析来深入了解CBD的重要机制和致病途径。 其具体目标是：1）为了证明与铍暴露的BeS和Be暴露对照相比，JAK/STAT途径和MAPK途径相关基因在CBD中被不适当地激活，使用qRT-PCR验证在微阵列分析中鉴定的这些潜在重要的CBD候选基因。2)通过使用Flp-in体外表达分析系统评估基因产物的过表达或使用siRNA“敲低”分析评估基因产物的减少，在功能上评估候选基因在JAK/STAT途径和MAPK途径中在CBD发病机制中的作用。3)研究差异基因是否与CBD（n=100）和BeS（n=100）在一个更大的单独的人群，从而揭示CBD的潜在的新的生物标志物。从这些数据中获得的见解将大大增加对CDB分子机制的理解，并可能导致开发潜在的新型生物标志物和新的研究靶点，作为CBD的潜在治疗方法。 公共卫生相关性：令人兴奋的初步研究表明，与暴露于Be的非疾病对照相比，CBD和BeS的外周血细胞表现出与这些过程的免疫功能和发病机制相关的差异基因表达谱。该提案旨在通过深入分析CBD中差异表达的候选基因，深入了解CBD中重要的机制和致病途径，重点关注Th 1免疫应答途径。这些结果可能会提高我们对CBD发展所涉及的因素的理解，决定预后的方面和治疗目标，作为与其他环境诱导疾病相关的免疫疾病的潜在应用模型。