This proposal describes a 5-year training program for the development of a career as a physician- scientist. The principal investigator has completed a PhD thesis at the University at Buffalo in tumor immunology, and Pediatric residency and Allergy/Immunology fellowship training at the University of California at San Diego. She will expand upon her scientific skills through a focused career development plan and training in molecular genetics as applied to immune dysregulation in pediatrics. Dr. Hal Hoffman is a Professor of Pediatrics and Medicine at UC San Diego and will mentor the principal investigator's scientific and career development. Dr. Hoffman is a globally recognized leader in autoinflammatory disorders. An advisory committee of scientists, including Dr. Kelly Frazer who has expertise in the role of genomics in pediatric disease, will provide additional career and project guidance. In addition, intensive workshops, seminars, journal clubs, and specific laboratory technique training will accompany ample protected research time. The academic environment in the Department of Pediatrics at UCSD supports the development of independent, translational investigators. Scientific investigations will focus on the genetic and immunoregulatory mechanisms of Periodic Fever, Aphthous stomatitis, Pharyngitis and Adenitis (PFAPA) syndrome, a systemic inflammatory disorder of childhood characterized by recurrent episodes of fever, oropharyngeal signs, cervical adenitis and leukocytosis in otherwise healthy children. The underlying etiology of PFAPA is unknown and therapies are limited; both are issues which negatively impact the quality of life for patients and their families. The specific goals of this project are: 1) to identify the genetic basis of PFAPA syndrome using DNA collected from families with multiple members that have a history of PFAPA, 2) to investigate the patterns of gene expression in tissue from PFAPA patients undergoing tonsillectomy with a focus on IL-1-related pathways and B cells, and 3) to evaluate the role of DNA methylation and histone acetylation events in tonsils as a regulatory mechanism in the pathogenesis of PFAPA.

Public Health Relevance

Non-infectious recurrent fevers are an under-recognized clinical symptom in pediatrics with significant effects on the quality of life for affected childre and their families. The proposed studies have direct significance for understanding the mechanisms of recurrent fever syndromes in children and may identify therapeutic targets.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Clinical Investigator Award (CIA) (K08)
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Study Section
National Institute of Child Health and Human Development Initial Review Group (CHHD)
Program Officer
Winer, Karen
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University of California, San Diego
Schools of Medicine
La Jolla
United States
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Hoffman, Hal M; Broderick, Lori (2018) JAK inhibitors in autoinflammation. J Clin Invest 128:2760-2762
Radhakrishna, Suhas M; Grimm, Amy; Broderick, Lori (2017) Novel mutation identified in severe early-onset tumor necrosis factor receptor-associated periodic syndrome: a case report. BMC Pediatr 17:108
Nakanishi, Hiroshi; Kawashima, Yoshiyuki; Kurima, Kiyoto et al. (2017) NLRP3 mutation and cochlear autoinflammation cause syndromic and nonsyndromic hearing loss DFNA34 responsive to anakinra therapy. Proc Natl Acad Sci U S A 114:E7766-E7775
Hoffman, Hal M; Broderick, Lori (2017) Editorial: It Just Takes One: Somatic Mosaicism in Autoinflammatory Disease. Arthritis Rheumatol 69:253-256
McGeough, Matthew D; Wree, Alexander; Inzaugarat, Maria E et al. (2017) TNF regulates transcription of NLRP3 inflammasome components and inflammatory molecules in cryopyrinopathies. J Clin Invest 127:4488-4497
Hoffman, Hal M; Broderick, Lori (2016) The role of the inflammasome in patients with autoinflammatory diseases. J Allergy Clin Immunol 138:3-14
Broderick, Lori (2016) Recurrent Fevers for the Pediatric Immunologist: It's Not All Immunodeficiency. Curr Allergy Asthma Rep 16:2
Broderick, Lori; De Nardo, Dominic; Franklin, Bernardo S et al. (2015) The inflammasomes and autoinflammatory syndromes. Annu Rev Pathol 10:395-424
Qu, Chao; Bonar, Sheri L; Hickman-Brecks, Cynthia L et al. (2015) NLRP3 mediates osteolysis through inflammation-dependent and -independent mechanisms. FASEB J 29:1269-79
Broderick, Lori; Hoffman, Hal M (2014) cASCading specks. Nat Immunol 15:698-700

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