Unraveling the Molecular Function of Mosaic, a gene mediating immune dysregulation

揭示马赛克的分子功能，一种介导免疫失调的基因

• 批准号: 10433882
• 负责人: ALICE CHAN
• 金额: $ 20.73万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10433882
• 关键词: Addison' s disease; Address; Adrenal Gland Diseases; Advisory Committees; Affect; Alleles; Amino Acids; Animal Model; Autoimmune; Autoimmune Diseases; Autoimmunity; Binding; Biology; Bone Marrow; CD3 Antigens; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CRISPR/Cas technology; Canis familiaris; Cell Compartmentation; Cell physiology; Cells; Cellular biology; Childhood; Clinic; Clinical; Clinical Immunology; Code; Colitis; Collection; Communities; Computer Analysis; Critical Pathways; Data; Data Set; Defect; Development; Development Plans; Disease; Doctor of Philosophy; Dog Diseases; Ducks; Educational workshop; Effector Cell; Environment; Experimental Autoimmune Encephalomyelitis; FOXP3 gene; Faculty; Fostering; Foundations; Generations; Genes; Goals; Growth; Haplotypes; Hepatitis; Homeostasis; Human; Hypersensitivity; IL7 gene; Immune; Immune Tolerance; Immune system; Immunology; In Vitro; Inherited; K-Series Research Career Programs; Knock-in; Knock-out; Knowledge; Lead; Leucine; Link; LoxP-flanked allele; Lymphoid Tissue; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Memory; Mentorship; Modeling; Molecular; Mosaicism; Mus; Mutation; Nova Scotia; Nuclear Localization Signal; Paper; Pathogenesis; Pathogenicity; Pathway interactions; Patient Care; Patients; Pattern; Peripheral; Phenotype; Physicians; Play; Point Mutation; Polyglandular Autoimmune Syndrome Type I; Proline; Proteins; Publications; Regulatory T-Lymphocyte; Reporter; Research; Research Personnel; Research Proposals; Rheumatology; Role; Scientist; Signal Transduction; Solid; Syndrome; System; T memory cell; T-Lymphocyte; Technical Expertise; Training; Translating; Uveitis; Vertebrates; Work; base; career; career development; causal variant; clinical practice; cohort; cytokine; cytopenia; early onset; genome-wide; high dimensionality; immune function; immunoregulation; improved; in vivo; insight; interest; knockout gene; mouse model; mutant; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; pediatric department; programs; reconstitution; skills; success; symposium; tool; transcriptome sequencing; tumor

PROGRAM SUMMARY/ABSTRACT Immune regulation plays a critical role in tolerance and tumor surveillance. Insight into these mechanisms have arisen from studies on patients and animal models with mutations in FOXP3 for IPEX syndrome or AIRE for APS-1 syndrome. Understanding these mechanisms have led to novel therapies. Dr. Alice Chan’s career focus is to understand perturbations in immune regulation by studying animal models and patients, with the goal of translating the biology into clinical practice to improve patient care. Her interest in immune dysregulation started from her research work during her MD/PhD training. She then became board-certified in both Pediatric Rheumatology and Allergy/Immunology to care for patients with immune dysregulation disorders in a clinic she established for this unique patient cohort. Studies on these patients have led to several publications, including a first author paper. To continue her career development, she has proposed a 5-year career development plan to transition her to become a physician scientist with an independent research program. The plan cultivates both professional and scientific skills as well as an independent research portfolio. She will have direct mentorship by Dr. Mark Anderson and her advisory committee, which includes a carefully curated group of well-recognized scientists and physicians with expertise in T cell biology and clinical immunology. Her proposed coursework, conferences and workshops will help her achieve new technical expertise and refine professional skills. Her research proposal focuses on unraveling the molecular mechanisms behind a novel gene, Mosaic, which has been identified as the causal gene for a multiorgan system autoimmunity in a subset of canines. Given that Mosaic is a highly conversed protein among vertebrates, Dr. Chan has developed several Mosaic mouse models with preliminary data supporting a role in T cell function. The research proposal has 3 aims: Aim 1 defines the mechanism(s) by which Mosaic maintains peripheral T cell homeostasis. Aim 2 defines the molecular pathway(s) through which Mosaic modifies Th17 effector function. Aim 3 determines the ability of defects in Mosaic to drive autoimmunity. The proposed aims will not only develop scientific skills but also build a research portfolio to establish herself as an independent investigator. Her training will be at UCSF which is an ideal environment that supports physician scientists. The Department of Pediatrics has a long track record of fostering the career development of young faculty. The UCSF immunology community includes a broad collection of investigators who are leaders in a wide breadth of research arenas that will accelerate Dr. Chan’s personal and professional growth. In summary at the completion of this career development award, Dr. Chan will have cultivated the necessary skills to launch her own independent research program. This proposal builds on her long-standing research and clinical interest in immune dysregulation and will foster her success as a physician scientist.

数据摘要/摘要 免疫调节在耐受和肿瘤监视中起着关键作用。对这些机制的深入了解， 源于对FOXP 3突变的IPEX综合征或AIRE突变的患者和动物模型的研究 APS-1综合征。了解这些机制导致了新的治疗方法。Alice Chan博士的职业生涯 重点是通过研究动物模型和患者来了解免疫调节的扰动， 目标是将生物学转化为临床实践，以改善患者护理。 她对免疫失调的兴趣始于她在MD/PhD培训期间的研究工作。然后她 获得儿科流变学和过敏/免疫学的委员会认证，以照顾患有 她为这个独特的患者群体建立的诊所中的免疫失调疾病。研究这些 患者导致了几篇出版物，包括第一作者论文。 为了继续她的职业发展，她提出了一个5年职业发展计划， 成为一名拥有独立研究项目的医生科学家。该计划既培养专业人才， 科学技能以及独立的研究组合。她将得到马克博士的直接指导 安德森和她的顾问委员会，其中包括一个精心策划的知名科学家小组 以及具有T细胞生物学和临床免疫学专业知识的医生。她建议的课程，会议 和研讨会将帮助她获得新的技术专长和完善专业技能。 她的研究计划侧重于解开一种新基因Mosaic背后的分子机制， 已被鉴定为犬科动物亚群中多器官系统自身免疫的致病基因。鉴于 Mosaic是一种在脊椎动物中高度转化的蛋白质， 初步数据支持T细胞功能中的作用。研究计划有三个目标：目标1 定义了Mosaic维持外周T细胞稳态的机制。目标2定义了 Mosaic通过其改变Th 17效应子功能的分子途径。目标3决定了 马赛克的缺陷来驱动自身免疫拟议的目标不仅将发展科学技能， 一份研究组合，以使自己成为一名独立调查员。 她的培训将在UCSF，这是一个理想的环境，支持医生科学家。部 儿科有促进年轻教师的职业发展的长期记录。大学旧金山 免疫学社区包括广泛的研究人员，他们是广泛领域的领导者。 研究领域，这将加速陈博士的个人和专业成长。 总而言之，在完成这项职业发展奖后，陈博士将培养出必要的 她有能力开展自己的独立研究项目。这项建议建立在她长期的研究基础上 和免疫失调的临床兴趣，并将促进她作为一个医生科学家的成功。