Noncanonical NFkB Pathway-Mediated Mechanisms of Common Variable Immunodeficiency

常见变异性免疫缺陷的非典型 NFkB 通路介导机制

• 批准号: 9204388
• 负责人: Karin Chen
• 金额: $ 20.2万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9204388
• 关键词: Address; Adrenal gland hypofunction; Adult; Affect; Age of Onset; Antibodies; Antibody Formation; Antigens; Autoimmune Process; Autoimmunity; B Cell Proliferation; B-Lymphocytes; Bioinformatics; Biological Assay; C-terminal; Cell Maturation; Cell Survival; Cell physiology; Cells; Child; Child health care; Childhood; Clinic; Clinical; Clinical Sciences; Clinical Skills; Collaborations; Common Variable Immunodeficiency; Communities; Core Facility; Coupled; Data; Defect; Development; Diagnosis; Dimerization; Disease; Doctor of Philosophy; Environment; Etiology; Evolution; Family; Fellowship; Funding; Gene Expression; Gene Mutation; Genes; Genetic; Genetic Transcription; Genomics; Germ-Line Mutation; Goals; Health Sciences; Hospitals; Human; Human Genetics; Humoral Immunities; Hypersensitivity; Immune; Immune System Diseases; Immune system; Immunity; Immunology; Immunology procedure; Immunophenotyping; Impairment; Individual; Infection; Inflammation; Inflammatory Response; Institutes; Institution; International; Investigation; K-Series Research Career Programs; Laboratories; Lead; Leadership; Lymphocyte Function; Lymphoid; Mediating; Memory B-Lymphocyte; Mentors; Mentorship; Modality; Molecular; Molecular Analysis; Molecular Medicine; Mutation; NCI Scholars Program; NFKB2 gene; Nuclear Translocation; Pathogenesis; Pathway interactions; Patient Care; Patients; Pediatrics; Peripheral; Phenotype; Physicians; Population Genetics; Positioning Attribute; Predisposition; Proteins; Recurrence; Regulation; Research; Research Personnel; Research Project Grants; Research Training; Residencies; Resources; Role; SECTM1 gene; Sampling; Scientist; Signal Pathway; Signal Transduction; Syndrome; Technical Expertise; Testing; Thymus Gland; Training; Translating; Translational Research; Universities; Utah; Variant; Work; base; career; career development; clinical development; clinical diagnostics; cohort; congenital immunodeficiency; differential expression; dimer; early onset; exome sequencing; experience; genetic analysis; genetic variant; immune function; improved; innovation; insight; laboratory development; medical schools; meetings; mutant; next generation sequencing; novel; pediatric department; prevent; professor; programs; public health relevance; response; screening; skill acquisition; skills; transcription factor; transcriptome; transcriptome sequencing

 DESCRIPTION (provided by applicant): The Candidate: From my residency training in Pediatrics, through fellowship in Allergy and Immunology, to my current position as an Assistant Professor at the University of Utah, I worked towards the overarching goal of improving diagnosis and treatment by understanding the genetic and pathophysiologic basis of primary immunodeficiency diseases (PIDs). I am committed to an academic career as a physician scientist, elucidating disease mechanisms and translating discoveries in genetics to improving the care of patients with PIDs. I have demonstrated this commitment based on my development of outstanding mentorship at my institution, and have generated two first-authored, high-impact research articles involving the genetic investigation of a form of common variable immunodeficiency, and a population genetic analysis of RAG mutations associated with PIDs. Further, I have developed collaborations with key investigators within and outside of the University to maximize both relevant patient samples and efforts involving functional and genetic analyses of PIDs. Institutional Environment: I work in the laboratories of both Lynn Jorde, PhD, (Department of Human Genetics) and Guy Zimmerman, MD, (Molecular Medicine Program) and both laboratories are situated within the Eccles Institute of Human Genetics building located on the University of Utah Health Sciences campus. The University of Utah is an institution rich with resources to support physician scientists and includes the Health Sciences Center, which includes both a network of patient clinics and an adult hospital at the School of Medicine; a pediatric tertiary hospital; and support for researchers including vast core facility resources and the University of Utah Center for Clinical and Translational Science (CCTS). My research environment is ideal for support of my research project and training aims. The Department of Pediatrics has demonstrated a commitment to support my career goals by providing intensive mentoring and training through the departmental Pediatric Clinical and Translational (PCAT) Research Scholars Program as well as being selected as a scholar in the K12 Child Health Research Career Development Award Program. Career Development and Training: My short-term career objective is to gain an understanding of the genetic and molecular pathogenesis of CVID caused by defects in the noncanonical NF-B pathway. My longterm career objective includes development into an R01-funded, independent principle investigator who is able to lead multiple projects in translational investigations of CVID and other PIDs. I crafted my career development activities together with an outstanding mentorship team with two primary co-mentors and three advisors to build on my past research experiences and to address new skill development. My scientific training includes development of laboratory bench skills in functional immune assays utilizing human cells, development of my technical skills and understanding of bioinformatics in next-generation sequencing modalities, as well as development of clinical diagnostics for improved immunophenotyping of PID patients. My professional development and training includes continued development of my leadership skills to improve my ability to manage an independent laboratory, as well as continued development of collaborative relationships in the national and international PID community. The training plan includes regular meetings with my co-mentors, didactic courses, seminars, and national/international meetings. Project Description: We recently identified NFKB2 (NF-B2), and its signaling pathway, the noncanonical NF-B pathway, as the etiology of a form of CVID. Our preliminary data have demonstrated that the NFKB2 mutations in our CVID cohort result in reduced NF-κB2/p52 nuclear translocation. The resultant phenotype includes early age-onset of panhypogammaglobulinemia, autoimmune features and adrenal insufficiency. Little is known about the direct downstream signaling and transcriptional effects of NF-B2 in humans, and why mutations in NFKB2 may result in the specific CVID phenotype. We aim to delineate the effects of NFKB2 mutations at the transcriptional, molecular, and cellular levels to better understand the contribution of the noncanonical NF-B pathway in maintaining humoral immunity. First, we will perform functional B cell assays to identify defects contributing to poor antibody production. Second, we will perform RNA-Seq to determine differences in gene expression caused by mutant NFKB2, in order to identify the targets that have protein level changes. Using RNA-Seq, we will identify the major signaling pathways regulated by NF-B2 and confirm alterations at the protein level. Finally, we will perform exome sequencing followed by state-of-the-art bioinformatic analysis to investigate pathways regulated by NF-B2, identify and phenotype additional CVID patients with noncanonical NF-κB defects, and discover new disease-causing variants. The research proposed here will allow me to combine my clinical skills with thorough training in cutting-edge genomic and molecular analysis. It will position me at the forefront of the genetic revolution.

 描述（由申请人提供）： 候选人：从儿科住院医师培训，到过敏和免疫学研究员，再到目前在犹他大学担任助理教授，我通过以下方式努力实现改善诊断和治疗的总体目标：了解原发性免疫缺陷疾病 (PID) 的遗传和病理生理学基础 我致力于作为一名医师科学家的学术生涯，阐明疾病机制并将遗传学的发现转化为改善疾病的方法。基于我在所在机构的出色指导，我已经证明了这一承诺，并发表了两篇第一作者的高影响力研究文章，涉及一种常见变异免疫缺陷的遗传研究，以及一篇此外，我还与大学内外的主要研究人员开展了合作，以最大限度地提高相关患者样本和机构环境的功能和遗传分析：我在这两个实验室工作。 Lynn Jorde 博士（人类遗传学系）和 Guy Zimmerman 医学博士（分子医学项目）和两个实验室均位于犹他大学健康科学校区的埃克尔斯人类遗传学研究所大楼内。一个拥有丰富资源来支持医师科学家的机构，包括健康科学中心，其中包括患者诊所网络和医学院的成人医院，并为研究人员提供支持，包括庞大的核心设施资源和犹他大学临床和转化科学中心 (CCTS) 我的研究环境非常适合支持我的研究项目和培训目标，儿科部门通过提供强化指导和培训来支持我的职业目标。儿科临床和转化 (PCAT) 研究学者计划以及被选为 K12 儿童健康研究职业发展奖励计划的学者：我的短期职业目标是了解遗传和分子。我的长期职业目标包括发展成为一名有能力的 R01 资助的独立首席研究员。 为了领导 CVID 和其他 PID 转化研究的多个项目，我打造了自己的职业生涯。 与由两名主要导师和三名顾问组成的杰出导师团队一起开展开发活动，以我过去的研究经验为基础，并解决新技能的发展问题。我的技术技能和对下一代测序模式中生物信息学的理解，以及开发改善 PID 患者免疫表型的临床诊断方法 我的专业发展和培训包括持续发展我的领导技能，以提高我管理独立实验室的能力，还有随着国家和国际 PID 界合作关系的持续发展，培训计划包括与我的共同导师定期举行会议、教学课程、研讨会和国家/国际会议。及其信号通路，即非典型 NF-κB 通路，作为一种 CVID 的病因学，我们的初步数据表明，我们的 CVID 队列中的 NFKB2 突变导致了 CVID 的减少。 NF-κB2/p52 核易位所产生的表型包括早年出现的全低丙种球蛋白血症、自身免疫特征和肾上腺功能不全，而人们对 NF-κB2 的直接下游信号传导和转录效应以及为什么 NFKB2 可能发生突变知之甚少。我们的目标是在转录、分子和细胞水平上描述 NFKB2 突变的影响，以更好地了解 CVID 表型。首先，我们将进行功能性 B 细胞测定，以确定导致抗体产生不良的缺陷；其次，我们将进行 RNA 测序以确定突变 NFKB2 引起的基因表达差异。为了识别出蛋白质水平发生变化的靶点，我们将识别 NF-κB2 调节的主要信号通路，并确认蛋白质水平上的变化。最后，我们将进行外显子组测序。最先进的生物信息学分析，以研究 NF-κB2 调节的通路，识别具有非典型 NF-κB 缺陷的其他 CVID 患者并进行表型分析，并发现新的致病变异。这里提出的研究将使我能够结合我的研究。临床技能以及尖端基因组和分子分析方面的全面培训将使我处于遗传革命的最前沿。