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Delineation of a cytokine gene regulatory network and rewiring in disease

细胞因子基因调控网络的描绘和疾病中的重新布线

基本信息

批准号：
8867410
负责人：
Juan Ignacio Fuxman Bass
金额：
$ 9万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8867410
关键词：
Address Affect Alleles American Area Arthritis Autoimmune Diseases Autoimmunity Award Binding Binding Sites Bioinformatics Biological Assay Biological Response Modifiers Cell Line Cells Chronic Collaborations Complement Complex Cues Cytokine Gene Cytokine Signaling DNA-Protein Interaction Data Data Analyses Diamond Disease Enhancers Environment Failure Follow-Up Studies Gene Expression General Transcription Factors Genes Genetic Transcription Goals Health Hereditary Disease Human Human Genetics Hybrids Immune Immune System Diseases Immune response Immunology Infection Inflammatory Response Institution Knock-out Laboratories Lead Leadership Learning Link Malignant Neoplasms Mentors Modeling Mutation Nucleic Acid Regulatory Sequences Oranges Pathologic Pathology Pathway interactions Phase Play Point Mutation Positioning Attribute Predisposition Preparation Process Production Public Health Publications Regulation Regulator Genes Research Research Personnel Resources Role Secure Signal Transduction Signaling Protein System Systemic Lupus Erythematosus Systems Biology Techniques Testing Training Training Activity Transcriptional Regulation United States National Institutes of Health Untranslated RNA Validation Work Writing Yeasts career career development cytokine experience follow-up genome editing genome wide association study in vivo innovation insight interest mutant new therapeutic target novel overexpression programs promoter public health relevance response skills therapeutic target tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): My long term foal is to become an independent investigator at a major American research institution, developing cutting-edge research at the interface between immunology and systems biology. To achieve this goal my immediate objectives are: (1) to produce innovative, high quality research that will result in high impact publications that are independent of my mentor's lines of research, (2) to acquire a new set of skills in bioinformatics, complex data analyses, immunology, and genome editing approaches to complement my existing background. Obtaining the prestigious NIH pathway to independence award would bolster my career opportunities and provide me with the means to develop and mature my own research program, plus acquire the additional training I need to succeed as an independent researcher. The proposed research encompasses my major scientific interests: integrating immune regulation with systems biology approaches to study gene expression. Cytokines are cell-to-cell signaling proteins that play fundamental roles in delineating immune responses. Cytokine production is highly regulated at the transcriptional level, and failure to express them appropriately often results in several pathologies such as autoimmune diseases, cancer and susceptibility to infections. After more than three decades of research, many aspects of cytokine expression are still not well understood, and transcriptional regulation of cytokine gene expression has not been explored on a systems level. My research will delineate the first gene-centered cytokine gene regulatory network (GRN) by comprehensively identifying the transcription factors (TFs) that regulate cytokine genes. To do so, I will first identify the Ts that can bind to the promoter and other known regulatory regions for all human cytokines by directly testing for protein-DNA interactions (PDIs) using high-throughput yeast one-hybrid (eY1H) assays, recently developed in the Walhout lab. I will model the PDIs detected into a GRN and will integrate this GRN with publicly available expression data to define which TFs positively or negatively regulate cytokine expression. These analyses together with functional validation assays in knockout cell lines will identify cytokine regulators linking them to their functional role and relevance in disease. Non coding mutations are at the core of many human genetic diseases and constitute 90% of all mutations identified in genome-wide association studies. For instance, mutations in cytokine regulatory regions have been associated with cancer, higher susceptibility to infections, chronic arthritis and systemic lupus erythematosus. These mutations can result in loss or gain of transcription factor binding sites. Assays to test th PDI changes are labor intensive and limited to a few dozen TFs. Thus, I propose to use a novel eY1H pipeline to systematically interrogate for PDI changes that result as a consequence of disease-associated mutations in cytokine regulatory regions. Findings from this experimental approach will be further validated in immune cell lines and will provide mechanistic insights and therapeutic targets for many immune related diseases. The cross-disciplinary program I propose requires that I obtain additional training in multiple areas of research that will complement my background and will provide me with state-of-the-art tools for my future research as an independent investigator. I have identified Dr. Walhout and Dr. Fitzgerald as ideal mentors to carry out my proposed work, together with Dr. Wolfe and Dr. Myers as collaborators, with highly complementary expertise. Working in collaboration with these world-renowned researchers in a stimulating environment such as that of UMMS, together with the training activities my mentoring committee and I have planned for the mentored phase of the award, will enable me to (1) become more proficient in state-of-the-art immunology techniques and learn up-to-date immunology concepts, (2) acquire bioinformatics and complex data analysis skills, and (3) learn genome editing approaches, all necessary for the interpretation and validation of the proposed work. This scientific expertise will be complemented with career development seminars and activities to acquire the mentoring, leadership, grantsmanship and writing skills I will need to succeed as an independent investigator. Securing this award would place me in an ideal position to capitalize on my experience to date in the Walhout laboratory, while allowing me to define my own research niche. This award will lead to a better understanding of how immune genes are regulated in normal and pathologic conditions, which will have a broad impact on public health.