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: 10653017
• 负责人: ALICE CHAN
• 金额: $ 20.57万
• 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/10653017
• 关键词: Acceleration; Addison' s disease; Adrenal Gland Diseases; Advisory Committees; Affect; Alleles; Amino Acids; Animal Model; Autoimmune; Autoimmune Diseases; Autoimmunity; Binding; Biology; Board Certification; Bone Marrow; Breeding; 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; Leucine; Link; LoxP-flanked allele; Lymphoid Tissue; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Mediator; Memory; Mentorship; Modeling; Molecular; Mus; Mutation; Nova Scotia; Nuclear Localization Signal; Organ; Paper; Pathogenesis; Pathogenicity; Pathway interactions; Patient Care; Patients; Pattern; Peripheral; Phenotype; Physicians; Play; Point Mutation; Polyglandular Autoimmune Syndrome Type I; Proliferating; Proline; Proteins; Publications; Regulatory T-Lymphocyte; Reporter; Research; Research Personnel; Research Proposals; Rheumatology; Role; Scientist; Signal Transduction; Solid; Syndrome; T cell infiltration; T memory cell; T-Lymphocyte; Technical Expertise; Training; Translating; Uveitis; Vertebrates; Work; autosome; body system; career; career development; causal variant; clinical practice; cohort; cytokine; cytopenia; early onset; genome-wide; immune function; immunoregulation; improved; in vivo; insight; interest; knockout gene; mosaic; mosaic variant; mouse model; multidimensional data; 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.

程序摘要/摘要 免疫调节在耐受性和肿瘤监测中起关键作用。对这些机制的了解 来自对IPEX综合征Foxp3突变的患者和动物模型的研究引起的 APS-1综合征。了解这些机制导致了新的疗法。爱丽丝·陈博士的职业 重点是通过研究动物模型和患者，了解免疫调节的扰动 将生物学转化为临床实践以改善患者护理的目标。 她对免疫失调的兴趣始于在MD/博士培训期间的研究工作。然后她 在儿科风湿病学和过敏/免疫学中获得了董事会认证，以照顾患者 她为这个独特的患者队列建立的诊所中的免疫失调障碍。这些研究 患者导致了一些出版物，其中包括第一篇作者论文。 为了继续她的职业发展，她提出了一项为期5年的职业发展计划，将她过渡到 成为独立研究计划的物理科学家。该计划既培养专业人士又 科学技能以及独立的研究组合。她将获得马克博士的直接精神训练。 安德森及其咨询委员会，包括一群精心策划的良好认可的科学家 以及具有T细胞生物学和临床免疫学专业知识的医生。她提出的课程，会议 讲习班将帮助她获得新的技术专长和完善专业技能。 她的研究提案着重于揭开新基因Mosaic背后的分子机制，该机制是Mosaic，该基因 已被确定为在犬类子集中自动免疫的多器系统自身免疫的因果基因。鉴于 马赛克是脊椎动物中高度转化的蛋白 具有初步数据的模型支持在T细胞功能中的作用。研究建议有3个目标：目标1 定义了镶嵌物保持周围T细胞稳态的机制。 AIM 2定义 镶嵌物通过其修饰Th17效应函数的分子途径。 AIM 3决定了 马赛克缺陷以驱动自身免疫性。拟议的目标不仅会发展科学技能，而且还将建立 一个研究组合，以建立自己为独立研究者。 她的培训将在UCSF进行，这是一个支持物理科学家的理想环境。部门 儿科的悠久记录是促进年轻教职员工的职业发展。 UCSF 免疫学社区包括广泛的调查员，他们是领导者 研究领域将加速Chan博士的个人和专业成长。 总而言之，该职业发展奖完成后，Chan博士将培养必要的 启动自己的独立研究计划的技能。这项建议是基于她的长期研究 以及对免疫失调的临床兴趣，并将促进她作为物理科学家的成功。

项目成果

Primary immune regulatory disorders: a growing universe of immune dysregulation.

• DOI: 10.1097/aci.0000000000000689
• 发表时间: 2020-12
• 期刊: Current opinion in allergy and clinical immunology
• 影响因子: 2.8
• 作者: Chan AY;Torgerson TR
• 通讯作者: Torgerson TR