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：从我在儿科住院医师培训，通过在过敏和免疫学奖学金，我目前的位置作为助理教授在犹他州的大学，我对提高诊断和治疗的首要目标，通过了解原发性免疫缺陷疾病（PID）的遗传和病理生理基础。我致力于作为一名医生科学家的学术生涯，阐明疾病机制，并将遗传学发现转化为改善PID患者的护理。我已经证明了这一承诺的基础上，我在我的机构发展的优秀导师，并产生了两个第一作者，高影响力的研究文章，涉及一种常见的可变免疫缺陷的遗传调查，和人群遗传分析RAG突变与PID。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涉及PID功能和遗传分析的努力。体制环境：我在林恩乔德博士（人类遗传学系）和盖伊齐默尔曼博士（分子医学项目）的实验室工作，这两个实验室都位于犹他州大学健康科学校区的埃克尔斯人类遗传学研究所大楼内。犹他州大学是一个拥有丰富资源的机构，以支持医生科学家，包括健康科学中心，其中包括一个网络的病人诊所和一个成人医院在医学院;儿科三级医院;和支持研究人员，包括巨大的核心设施资源和犹他州中心临床和转化科学（CCTS）的大学。我的研究环境非常适合支持我的研究项目和培训目标。儿科部门已经证明了通过部门儿科临床和转化（PCAT）研究学者计划提供密集的指导和培训，以及被选为K12儿童健康研究职业发展奖计划的学者，以支持我的职业目标的承诺。职业发展和培训：我的短期职业目标是了解非经典NF-κ B B通路缺陷引起的CVID的遗传和分子发病机制。我的长期职业目标包括发展成为R 01资助的独立的主要调查员， 领导CVID和其他PID翻译研究的多个项目。我精心打造了我的事业 发展活动与一个优秀的导师团队，两个主要的共同导师和三个顾问，以建立在我过去的研究经验，并解决新的技能发展。我的科学培训包括利用人类细胞进行功能性免疫测定的实验室工作台技能的发展，我的技术技能的发展和对下一代测序模式中生物信息学的理解，以及为改善PID患者的免疫表型开发临床诊断。我的专业发展和培训包括继续发展我的领导技能，以提高我管理独立实验室的能力，以及继续发展国内和国际PID社区的合作关系。培训计划包括与我的共同导师定期会议，教学课程，研讨会和国家/国际会议。项目描述：我们最近鉴定了NF-κ B 2（NF-κ B 2）及其信号传导途径，即非经典NF-κ B B途径，作为一种形式CVID的病因.我们的初步数据表明，在我们的CVID队列中，NF-κ B2突变导致NF-κB2/p52核转位减少。由此产生的表型包括早期全低丙种球蛋白血症、自身免疫特征和肾上腺功能不全。关于NF-κ B2在人类中的直接下游信号传导和转录作用以及NF κ B2突变为何可能导致特异性CVID表型知之甚少。我们的目的是描述NF κ B 2突变在转录、分子和细胞水平上的作用，以更好地理解非经典NF κ B B通路在维持体液免疫中的作用。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-Seq以确定突变NFKB 2引起的基因表达差异，以确定具有蛋白质水平变化的靶标。使用RNA-Seq，我们将确定NF-κ B2调控的主要信号通路，并确认蛋白质水平的改变。最后，我们将进行外显子组测序，然后进行最先进的生物信息学分析，以研究NF-κ B 2调节的途径，鉴定和表型其他非典型NF-κB缺陷的CVID患者，并发现新的致病变异。这里提出的研究将使我联合收割机结合我的临床技能与尖端基因组和分子分析的全面培训。它将使我站在基因革命的最前沿。