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-?B2/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-?B 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.

Public Health Relevance

Common variable immunodeficiency (CVID) is one of the most commonly treated primary immune deficiencies, but the gene mutations which have been identified account for fewer than 15% of cases. We recently identified NFKB2 (NF-?B2), and its signaling pathway, the noncanonical NF-?B pathway, as the etiology of a form of CVID. 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, which will then provide more effective disease screening and improved targets for treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AI116909-04
Application #
9416912
Study Section
Allergy, Immunology, and Transplantation Research Committee (AITC)
Program Officer
Gondre-Lewis, Timothy A
Project Start
2015-02-01
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Utah
Department
Pediatrics
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Kumánovics, Attila; Lee, Yu Nee; Close, Devin W et al. (2017) Estimated disease incidence of RAG1/2 mutations: A case report and querying the Exome Aggregation Consortium. J Allergy Clin Immunol 139:690-692.e3
John, Tami; Walter, Jolan E; Schuetz, Catherina et al. (2016) Unrelated Hematopoietic Cell Transplantation in a Patient with Combined Immunodeficiency with Granulomatous Disease and Autoimmunity Secondary to RAG Deficiency. J Clin Immunol 36:725-32