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My research program focuses on investigating inherited human diseases to provide insight into molecular mechanisms of disease. Our initial studies focused on familial cold autoinflammatory syndrome in which we positionally cloned a novel gene using DNA from affected individuals and controls to identify gain of function missense mutations as the cause of this disease (Nature Genetics, 2001). This gene, which we named CIAS1, now known as NLRP3, is expressed in peripheral blood leukocytes and encodes a protein we termed cryopyrin, also known as NLRP3, a crucial component of the inflammasome.

Our identification of this rare disease gene led to the discovery of the inflammasome, which has implications not only for patients with cryopyrin-associated periodic syndromes but also for gout, occupational lung disease, as well as diabetes, and atherosclerosis. We subsequently identified and implicated inflammasome mediated IL-1β as a crucial disease mediator, and performed studies that led to the novel treatment of cryopyrin-associated periodic syndromes (CAPS) patients with IL-1 targeted therapy (Lancet, 2004, Arthritis & Rheumatism, 2008). IL-1 targeted therapy is now the first line and most effective therapy for this previously untreatable disease.

To understand the role of the inflammasome in disease, we have developed 7 novel transgenic, knockout, and knockin mouse models to study immune and inflammatory responses in vivo, and ex vivo using cells harvested or cultured from these mice. These mice have been used to elucidate the disease pathophysiology and identify novel therapies for cryopyrin-associated periodic syndromes (CAPS) and have been instrumental in our understanding of the NLRP3 inflammasome (Immunity, 2009).

In addition to our focus on the inflammasome, we study patients with several other inherited disorders to identify mechanisms of disease pathogenesis using genetic and recombinant mouse approaches. Examples include the identification of MLP as a cause of dilated cardiomyopathy (Cell, 2002), EpCAM as the gene for congenital tufting enteropathy, an autosomal recessive diarrheal disease (Gastroenterology, 2008), and PLCG2 deletions as the genetic basis of an inherited disease characterized by cold urticaria and immune dysregulation (New Eng J Med, 2012). We have also studied inflammasome-mediated diseases without a known genetic link to the inflammasome such as non-alcoholic fatty liver disease (Hepatology, 2012).

Find a current list of the Hoffman lab's publications on PubMed.