RESEARCH: Numerous health benefits have been attributed to vitamin D. Understanding the molecular mechanisms responsible for its many benefits is essential for understanding its importance as a nutritional supplement. We made the seminal discovery that vitamin D regulates the expression of a key antimicrobial protein (AMP) referred to as cathelicidin or CAMP/LL-37. Since the mid-19th century, sources of vitamin D such as sunlight and cod liver oil were routinely used to treat tuberculosis. Our findings identified an important component to understanding a key mechanism by which macrophages may combat Mycobacterium tuberculosis and other pathogens in humans. The studies underway in my lab, utilize a combination of molecular and cellular biological approaches involving tissue culture and animal models to elucidate the biological and physiological importance of vitamin D in maintaining a healthy innate immune response. Immediate projects are focused on 1) understanding the transcriptional regulation of the CAMP gene with the goal of identifying additional pathways that may be regulated by nutritional factors; 2) identifying additional nutrients that regulate the CAMP gene; 3) utilizing the mouse model to elucidate the molecular mechanisms for vitamin D's ability to provide protection against infection and 4) elucidating the role of this pathway in the immune response of the elderly and identifying ways that supplementation may improve their immune response to infection.
SELECTED PUBLICATIONS: Gombart AF, Saito T, Koeffler HP. (2009) Exaptation of an ancient Alu short interspersed element provides a highly conserved vitamin D-mediated innate immune response in humans and primates. BMC Genomics 10:321.
Gombart AF, Bhan I, Borregaard N, Tamez H, Camargo Jr CA, Koeffler HP, Thadhani R. (2009) Low plasma level of cathelicidin antimicrobial peptide (hCAP18) predicts increased infectious disease mortality in patients undergoing hemodialysis. Clin Infect Dis. 48:418–424.
Adams JS, Ren S, Liu PT, Chun RF, Lagishetty V, Gombart AF, Borregaard N, Modlin RL, Hewison M. (2009) Vitamin D-directed rheostatic regulation of monocyte antibacterial responses. J Immunol. 182:4289-4295.
Gombart AF, Borregaard N, and Koeffler HP. (2005) Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3. FASEB J. 19:1067-1077.
Theilgaard-Mönch K, Jacobsen LC, Nielsen MJ, Rasmussen T, Udby L, Gharib M, Arkwright PD, Gombart AF, Calafat J, Moestrup SK, Porse BT, and Borregaard N. (2006) Haptoglobin is synthesized during granulocyte differentiation, stored in specific granules, and released by neutrophils in response to activation. Blood 108:353-361.
Gombart AF, Luong QT, and Koeffler HP. (2006) Vitamin D compounds: activity against microbes and cancer. Anticancer Res. 26:2531-2542.
Gombart AF, Grewal J, and Koeffler HP. (2007) ATF4 differentially regulates transcriptional activation of myeloid-specific genes by C/EBPε and C/EBPα. J. Leukoc Biol. 81:1535-1547.