Integrative Biology Approach to Identify and Characterize Roles of lncRNAs Associated with Psoriasis Pathology

识别和表征与银屑病病理学相关的 lncRNA 作用的综合生物学方法

• 批准号: 9371181
• 负责人: Lam Cheung Tsoi
• 金额: $ 10.42万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9371181
• 关键词: Affect; American; Appointment; Architecture; Autoimmune Diseases; Autoimmune Process; Basic Science; Bioinformatics; Biological; Biological Assay; Biological Process; Biology; Biomedical Research; Biometry; Catalogs; Cellular Structures; Chromatin; Chronic; Comorbidity; Complex; Computer Simulation; Coronary artery; Cutaneous; Data; Dermatologic; Dermatology; Development; Development Plans; Disease; Disease model; Disease susceptibility; Doctor of Philosophy; Economic Burden; Educational process of instructing; Educational workshop; Elderly; Elements; Enzyme-Linked Immunosorbent Assay; Enzymes; Epigenetic Process; Faculty; Flow Cytometry; Future; Gene Expression; Genes; Genetic; Genetic Transcription; Genetic study; Genomics; Genotype; Homing; Human; Immune; Immune system; Immunologics; Immunology; In Vitro; Inflammatory; Inflammatory Response; Knowledge; Learning; London; Lymphocyte; Machine Learning; Mediating; Medicine; Mentored Research Scientist Development Award; Mentors; Michigan; Modeling; Molecular; Molecular Profiling; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Play; Process; Production; Proteins; Psoriasis; Public Health; Quality of life; Quantitative Reverse Transcriptase PCR; Reaction; Recruitment Activity; Research; Research Project Grants; Role; Sampling; Science; Signal Transduction; Skin; Societies; Statistical Methods; Students; Supervision; Susceptibility Gene; Systems Biology; T-Lymphocyte; Technology; Testing; Therapeutic; Tissues; Training; Transcript; Translating; United States; Universities; Untranslated RNA; Validation; Visit; Work; base; candidate identification; career development; cell type; cohort; college; cytokine; drug discovery; experience; experimental study; fascinate; genetic association; genomic data; high dimensionality; human disease; human tissue; immunoregulation; insight; interest; keratinocyte; knock-down; laboratory experience; learning strategy; meetings; novel; novel marker; scaffold; skills; skin disorder; small hairpin RNA; statistical center; success; symposium; tool; transcriptome sequencing; transcriptomics

PROJECT SUMMARY/ABSTRACT Candidate After the completion of my Ph.D. in Bioinformatics, I joined the Center for Statistical Genetics at the University of Michigan (U-M) as research fellow and acquired extensive training in analysis on high- dimensional biological data. I uncovered a strong interest in studying the genetics and genomics of psoriasis when working with Dr. James Elder at the U-M, and I developed a fascination in understanding the functional roles of long non-coding RNAs (lncRNAs) in cutaneous diseases. I joined the Department of Dermatology at the U-M as a faculty in summer of 2015, with secondary appointments in the Department of Computational Medicine & Bioinformatics and the Department of Biostatistics. In addition, I direct the new Center for Cutaneous Bioinformatics within the Department of Dermatology, and serve to supervise and implement an analysis pipeline for studies investigating the immunological mechanisms for different skin diseases. Career Development Plan I aim to become a future leader in combining in silico discovery and bench experiments to advance biomedical research in autoimmune skin disorders. My objective in seeking a Mentored Research Scientist Development Award is to acquire the additional knowledge, training, and experience necessary for me to become an independent scholar in developing novel systems biology approaches to decipher the pathology and mechanisms of cutaneous diseases. The five year training proposed will provide knowledge and experience in aspects that are critical to my success, and they are: i) To develop knowledge and experimental skills in cutaneous biology --- achieved by guidance from Dr. Elder (investigative dermatology), intense research meetings/conferences, and practical laboratory experience in cutaneous research; ii) To develop knowledge and skills to study immunological systems of autoimmune skin diseases --- achieved by supervision from Dr. Johann Gudjonsson (skin immunology), attending formal Immunology courses and seminars, and earning laboratory experience from immunology experiments; iii) To advance skills in developing statistical and computational approaches --- accomplished by mentoring from Dr. Goncalo Abecasis (computational biologist), research meetings, and conducting research projects requiring advanced skills and knowledge in quantitative science; iv) To cultivate my professional development through enhancing scientific connections, grantsmanship skills, and educator portfolio --- achieved by establishing connections with colleagues during meetings, visiting King’s College London as scholar, attending a grantsmanship workshop and bootcamp, and learning mentoring skills through teaching formal classes and mentoring research students. Through the intensive and comprehensive training, I will be well grounded in conducting basic science experiments and also be able to capitalize my advanced knowledge in quantitative science to model mechanisms in cutaneous diseases. Research Project The research project will use psoriasis as a disease model to study the roles of lncRNAs in complex cutaneous disorders. I will test the hypotheses that (i): some lncRNAs are key causal elements and potentiate pathogenic inflammatory reactions in psoriasis development and (ii) by combining in silico predictions and in vitro validations we are able to provide comprehensive characterization of skin-expressing lncRNAs in keratinocytes and lymphocytes to infer their pathological implications for psoriasis. This work will demonstrate how we can take advantages of the genomic data to develop an integrative biology framework to provide novel biological insights and understand pathological roles of lncRNAs. Significance Psoriasis is a chronic immune-mediated skin disease with complex genetic architecture. It is estimated that over 4 million Americans and 100 million people worldwide suffer from this disease. While genetic association studies have revealed the disease loci are highly enriched in non-coding regions, it is very challenging to translate genetic signals to biologic effects. In fact, most of the causal genes have not yet been identified. Our preliminary results showed that lncRNA is a class of gene that has largely been understudied for their roles in psoriasis, and both genetic and transcriptomic data suggested they can play important functions in psoriasis pathogenesis. By combining in silico analysis and in vitro validation we can expand our knowledge of lncRNAs in skin biology, and generate important hypotheses for future experiments. The results of this project can also identify novel biomarkers, and ultimately assist in the therapeutic drug discovery.

项目摘要/摘要 在完成生物信息学博士学位后，我加入了统计遗传学中心 密歇根大学(U-M)担任研究员，并接受了广泛的高密度分析培训。 多维生物数据。我发现人们对牛皮癣的遗传学和基因组学有着浓厚的兴趣。 当我在密歇根大学与詹姆斯·埃尔德博士共事时，我对理解功能性 长非编码RNA(LncRNA)在皮肤病中的作用。我加入皮肤科是在 密歇根大学于2015年夏天成为一名教员，在计算学系担任二级职务 医学与生物信息学和生物统计学系。此外，我还指导了新的中心 皮肤科内的皮肤生物信息学，并负责监督和实施 为研究不同皮肤病的免疫学机制提供分析管道。 职业发展计划I的目标是成为硅胶发现和板凳相结合的未来领导者 推进自身免疫性皮肤病生物医学研究的实验。我的目标是寻求 导师研究科学家发展奖是为了获得额外的知识、培训和 成为发展新系统生物学的独立学者所需的经验 解释皮肤病的病理和机制的方法。五年培训 建议将提供对我的成功至关重要的方面的知识和经验，它们是：i) 发展皮肤生物学方面的知识和实验技能-在埃尔德博士的指导下实现 (皮肤病研究)、密集的研究会议和实验室实践经验 皮肤研究；ii)发展研究免疫系统的知识和技能 自身免疫性皮肤病-由Johann Gudjonsson博士(皮肤免疫学)监督实现， 参加正规免疫学课程和研讨会，并从免疫学中获得实验室经验 实验；iii)提高开发统计和计算方法的技能 由贡卡洛·阿贝卡斯博士(计算生物学家)的指导、研究会议和 开展需要数量科学方面的高级技能和知识的研究项目；iv)培养 我的职业发展通过加强科学联系，手腕技能，以及 教育家组合-通过在会议期间与同事建立联系，访问King‘s 伦敦大学，作为学者，参加了一个GRANTSING研讨会和训练营，并学习了指导技能 通过教授正规班级和辅导研究型学生。通过集约和全面的 经过培训，我将在进行基础科学实验方面打下良好的基础，并能够充分利用我的 对皮肤病的发病机制进行建模的定量科学方面的高级知识。 研究项目该研究项目将使用牛皮癣作为疾病模型来研究lncRNAs在 复杂的皮肤病。我将检验这样的假设：(I)：一些lncRNA是关键的因果元件，并且 增强银屑病发展中的致病性炎症反应和(Ii)通过在硅胶中联合使用 预测和体外验证我们能够提供皮肤表达的全面特征 角质形成细胞和淋巴细胞中的lncRNAs，以推断其在银屑病中的病理意义。这项工作将 演示我们如何利用基因组数据来开发综合生物学框架 提供新的生物学见解并理解lncRNAs的病理作用。 意义银屑病是一种慢性免疫介导的皮肤病，具有复杂的遗传结构。它是 据估计，超过400万美国人和全球1亿人患有这种疾病。而当 遗传关联研究表明，疾病基因座在非编码区高度丰富，这是非常 将遗传信号转化为生物效应具有挑战性。事实上，大多数致病基因还没有 确认身份。我们的初步结果表明，lncrna是一类在很大程度上没有得到充分研究的基因。 它们在银屑病中的作用，以及遗传和转录数据都表明它们可以发挥重要作用 在银屑病发病机制中的作用。通过将计算机分析和体外验证相结合，我们可以扩展我们的知识 在皮肤生物学中研究lncRNAs，并为未来的实验产生重要的假设。这样做的结果 该项目还可以识别新的生物标记物，并最终帮助治疗药物的发现。