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: 10246892
• 负责人: Lam Cheung Tsoi
• 金额: $ 9.9万
• 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/10246892
• 关键词: Affect; American; Appointment; Autoimmune; Autoimmune Diseases; Basic Science; Bioinformatics; Biological; Biological Assay; Biological Process; Biology; Biomedical Research; Biometry; Catalogs; Cellular Structures; Chromatin; Chronic; Complex; Coronary Arteriosclerosis; Cutaneous; Data; 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 response; Immune system; Immunologics; Immunology; In Vitro; Inflammatory; Inflammatory Response; Knowledge; Learning; London; Lymphocyte; Mediating; Medicine; Mentored Research Scientist Development Award; Mentors; Michigan; Modeling; Molecular; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Play; Process; Production; Proteins; Psoriasis; Public Health; Quality of life; Quantitative Reverse Transcriptase PCR; Reaction; 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; analysis pipeline; base; candidate identification; career development; causal variant; cell type; cohort; college; comorbidity; cytokine; drug discovery; experience; experimental study; fascinate; genetic architecture; genetic association; genomic data; high dimensionality; human disease; human tissue; immunoregulation; in silico; insight; interest; keratinocyte; knock-down; laboratory experience; machine learning method; meetings; novel; novel marker; recruit; 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.

项目概要/摘要 候选人完成博士学位后。在生物信息学领域，我加入了统计遗传学中心 密歇根大学 (U-M) 担任研究员，并接受了高级分析方面的广泛培训 多维生物数据。我对研究牛皮癣的遗传学和基因组学产生了浓厚的兴趣 当我在密歇根大学与 James Elder 博士一起工作时，我对理解函数式产生了浓厚的兴趣。 长非编码RNA（lncRNA）在皮肤疾病中的作用。我加入皮肤科的时间是 2015 年夏天在密歇根大学任教，并在计算系担任次要职位 医学与生物信息学以及生物统计学系。此外，我还领导新的中心 皮肤科内的皮肤生物信息学，并负责监督和实施 用于调查不同皮肤病免疫机制的研究的分析管道。 职业发展计划我的目标是成为未来结合计算机发现和实验的领导者 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 指导研究科学家发展奖旨在获得额外的知识、培训和 我成为开发新型系统生物学的独立学者所必需的经验 破译皮肤疾病的病理学和机制的方法。五年培训 提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) 发展皮肤生物学知识和实验技能——在埃尔德博士的指导下实现 （皮肤病学研究）、密集的研究会议和实际实验室经验 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 --- 在 Johann Gudjonsson 博士（皮肤免疫学）的监督下实现， 参加正式的免疫学课程和研讨会，并获得免疫学实验室经验 实验； iii) 提高开发统计和计算方法的技能 --- 通过 Goncalo Abecasis 博士（计算生物学家）的指导、研究会议和 开展需要定量科学高级技能和知识的研究项目； iv) 培养 通过加强科学联系、资助技能和 教育工作者的作品集——通过在会议期间与同事建立联系、参观国王学院来实现 伦敦学院作为学者，参加资助研讨会和训练营，并学习指导技能 通过教授正式课程和指导研究生。通过深入、全面的 通过培训，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知识 定量科学的先进知识可以模拟皮肤疾病的机制。 研究项目 该研究项目将使用银屑病作为疾病模型来研究 lncRNA 在疾病中的作用 复杂的皮肤疾病。我将测试以下假设：(i)：一些 lncRNA 是关键因果元素，并且 增强银屑病发展中的致病性炎症反应，并且（ii）通过在计算机中结合 通过预测和体外验证，我们能够提供皮肤表达的全面表征 角质形成细胞和淋巴细胞中的 lncRNA，以推断其对牛皮癣的病理意义。这项工作将 展示我们如何利用基因组数据来开发综合生物学框架 提供新颖的生物学见解并了解 lncRNA 的病理作用。 意义 牛皮癣是一种慢性免疫介导的皮肤病，具有复杂的遗传结构。这是 据估计，超过 400 万美国人和全世界 1 亿人患有这种疾病。尽管 遗传关联研究表明，疾病位点高度富集于非编码区， 将遗传信号转化为生物效应具有挑战性。事实上，大部分致病基因还没有被研究出来。 确定。我们的初步结果表明，lncRNA 是一类在很大程度上尚未得到研究的基因。 它们在牛皮癣中的作用，遗传和转录组数据表明它们可以发挥重要功能 在牛皮癣的发病机制中。通过结合计算机分析和体外验证，我们可以扩展我们的知识 lncRNA在皮肤生物学中的应用，并为未来的实验产生重要的假设。这样做的结果 项目还可以识别新型生物标志物，并最终协助治疗药物的发现。

项目成果

Retrospective pharmacogenetic study of psoriasis highlights the role of KLK7 in tumour necrosis factor signalling.

银屑病的回顾性药物遗传学研究强调了 KLK7 在肿瘤坏死因子信号传导中的作用。

• DOI: 10.1093/bjd/ljad332
• 发表时间: 2023
• 期刊: The British journal of dermatology
• 作者: Zhang,Haihan;Patrick,MatthewT;Tejasvi,Trilokraj;Sarkar,MrinalK;Wasikowski,Rachael;Stuart,PhilipE;Li,Qinmengge;Xing,Xianying;Voorhees,JohnJ;Ward,NicoleL;He,Kevin;Zhou,Xiang;Gudjonsson,JohannE;Nair,RajanP;Elder,JamesT;T
• 通讯作者: T

Relationship between genetically proxied vitamin D and psoriasis risk: a Mendelian randomization study.

遗传代理维生素 D 与牛皮癣风险之间的关系：孟德尔随机化研究。

• DOI: 10.1093/ced/llad095
• 发表时间: 2023
• 期刊: Clinical and experimental dermatology
• 影响因子: 4.1
• 作者: Bohmann,Patricia;Stein,MichaelJ;Konzok,Julian;Tsoi,LamC;Elder,JamesT;Leitzmann,MichaelF;Baumeister,Sebastian-Edgar;Baurecht,Hansjörg
• 通讯作者: Baurecht,Hansjörg