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.

项目概要/摘要 免疫调节在耐受性和肿瘤监测中发挥着关键作用。 来自对患有 IPEX 综合征的 FOXP3 突变或患有 AIRE 综合征的患者和动物模型的研究 了解这些机制为 Alice Chan 博士带来了新的治疗方法。 重点是通过研究动物模型和患者来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她在医学博士/博士培训期间的研究工作。 获得小儿风湿病学和过敏/免疫学委员会认证，以护理患有以下疾病的患者 她为这个独特的患者群体建立了一个诊所，研究免疫失调疾病。 患者发表了多篇论文，其中包括一篇第一作者论文。 为了继续她的职业发展，她提出了一个5年的职业发展计划，将她过渡到 成为一名具有独立研究计划的医师科学家该计划培养专业和人才。 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。 研讨会将帮助她获得新的技术专业知识并提高专业技能。 她的研究计划侧重于揭示一种新基因 Mosaic 背后的分子机制，该基因 已被确定为犬科动物亚群多器官系统自身免疫的致病基因。 马赛克是脊椎动物中高度转换的蛋白质，陈博士已培育出数种马赛克小鼠 具有支持 T 细胞功能作用的初步数据的模型 该研究提案有 3 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 改变 Th17 效应子功能的分子途径决定了 Aim 3 的能力。 所提出的目标不仅是培养科学技能，而且是建立机制。 一个让自己成为独立研究者的研究组合。 她将在加州大学旧金山分校接受培训，这是支持医师科学家的理想环境。 加州大学旧金山分校儿科在促进年轻教师的职业发展方面有着悠久的记录。 免疫学界包括广泛的研究人员，他们是各个领域的领导者 研究领域将加速陈博士的个人和专业成长。 总而言之，在完成此职业发展奖后，陈博士将培养必要的能力 该提案建立在她长期研究的基础上。 以及对免疫失调的临床兴趣，并将促进她作为一名医学科学家的成功。

项目成果

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

原发性免疫调节紊乱：免疫失调的范围不断扩大。

• 发表时间: 2020
• 作者: Chan, Alice Y;Torgerson, Troy R
• 通讯作者: Torgerson, Troy R