Antigen Presentation, Autoimmunity, Cell Biology, Cellular Immunity, Dendritic Cells, Diabetes, Gene Discovery, Gene Expressions, Gene Regulation, Gene Therapy, Immunological Tolerance, Immunology, Infectious Disease, Inflammation, Macrophage, Molecular Biology, RNA, RNA Splicing & Processing, Retrovirus, T Cells, Tolerance, Transcriptional Activation and Repression, Transgenic Mice
Genetics and Genomic Sciences [GGS], Immunology [IMM]
BSc, University of Guelph
PhD, Queen's University
Postdoctoral Fellowship, San Raffaele Scientific Institute
Specific Clinical/Research Interests:
Immunology; Immunological Tolerance; Infectious Disease; Inflammation; Antigen Presentation; Dendritic Cells; Autoimmunity; Diabetes; Molecular Biology; Gene Discovery; Gene Expressions; Gene Regulation; RNA; RNA Regulation; microRNA; Regulation of the Innate Immune System
Summary of Research Studies:
A major focus of our work is aimed at identifying factors that control immunity and tolerance, and utilizing this information for developing therapeutic strategies that can direct antigen-specific immune responses. We helped to identify some of the transcriptional programs that regulate dendritic cell differentiation and function (Miller et al. Nat Immunol 2012), and we discovered a pathway controlling the innate response to nucleic acids, which involves the microRNA miR-126, and the main VEGF receptor, VEGFR2 (Agudo et al. Nat Immunol 2014). We are now using a new technology we developed, called the Jedi, to probe the interactions between T cells and tissues at a granular level, and learning how the tissue controls immune responses (Agudo et al. Nat Biotech 2015). This work has important implications for the development of autoimmunity as well as cancer immunology.
Our lab also has a strong emphasis in the generation of new technologies for experimental and therapeutic applications. We led the development of a novel gene targeting technology, which is now widely used for enhancing vector and virus-based drugs in applications ranging from the treatment of genetic diseases to cancer therapy to viral vaccines (Brown et al. Nat Med 2006, Brown et al. Nat Biotech 2007, Brown and Naldini. Nat Rev Gen 2009). We also developed the first genome-wide technology to measure miRNA activity and function at single cell resolution (Mullokandov, Baccarini, Ruzo et al. Nat Meth 2012), and aided in the invention of an improved method for deep sequencing small RNAs (Jayaprakash et al. Nucl Acid Res 2011). Recently, we helped develop a new platform for predicting the immune systems response to 100s of drugs (Kidd, Wroblewska et al. Nat Biotech. In Press).
Postdoctoral and graduate projects are available involving: (i) the study of microRNA and circular RNA regulation in antigen presenting cells, (ii) the discovery of novel gene expression networks in the immune system, and (iii) the development of therapeutic strategies for modulating immunity and tolerance.
Salmon H, Idoyaga J, Rahman A, Leboeuf M, Remark R, Jordan S, Casanova-Acebes M, Khudoynazarova M, Agudo J, Tung N, Chakarov S, Rivera C, Hogstad B, Bosenberg M, Hashimoto D, Gnjatic S, Bhardwaj N, Palucka AK, Brown BD, Brody J, Ginhoux F, Merad M. Expansion and Activation of CD103(+) Dendritic Cell Progenitors at the Tumor Site Enhances Tumor Responses to Therapeutic PD-L1 and BRAF Inhibition. Immunity 2016 Apr; 44(4).
Agudo J, Brown BD. Silence of the ROS. Immunity 2016 Mar; 44(3).
Brown BD, Merad M. Authorship: Archives and citation miss equal authors. Nature 2015 Dec; 528(7582).
Agudo J, Ruzo A, Park ES, Sweeney R, Kana V, Wu M, Zhao Y, Egli D, Merad M, Brown BD. GFP-specific CD8 T cells enable targeted cell depletion and visualization of T-cell interactions. Nature Biotechnology 2015 Dec; 33(12): 1287-1292.
Kidd BA *, Wroblewska A *, Boland MR, Agudo J, Merad M, Tatonetti NP, Brown BD *, Dudley JT *. Mapping the effects of drugs on the immune system. Nature Biotechnology 2016 Jan; 34(1): 47-54.
Mulero-Navarro S, Sevilla A, Roman AC, Lee DF, D'Souza SL, Pardo S, Riess I, Su J, Cohen N, Schaniel C, Rodriguez NA, Baccarini A, Brown BD, Cavé H, Caye A, Strullu M, Yalcin S, Park CY, Dhandapany PS, Yongchao G, Edelmann L, Bahieg S, Raynal P, Flex E, Tartaglia M, Moore KA, Lemischka IR, Gelb BD. Myeloid Dysregulation in a Human Induced Pluripotent Stem Cell Model of PTPN11-Associated Juvenile Myelomonocytic Leukemia. Cell Reports 2015 Oct 20; 13(3): 504-15.
Israelow B *, Mullokandov G *, Agudo J, Sourisseau M, Bashir A, Maldonado AY, Dar AC, Brown BD *, Evans MJ *. Hepatitis C virus genetics affects miR-122 requirements and response to miR-122 inhibitors. Nature Communications 2014 Nov; 5: 5408.
Agudo J, Ruzo A, Tung N, Salmon H, Leboeuf M, Hashimoto D, Becker C, Garrett-Sinha LA, Baccarini A, Merad M, Brown BD. The miR-126-VEGFR2 axis controls the innate response to pathogen-associated nucleic acids. Nature Immunology 2013 Nov;.
Miller JC, Brown BD, Shay T, Gautier EL, Jojic V, Cohain A, Pandey G, Leboeuf M, Elpek KG, Helft J, Hashimoto D, Chow A, Price J, Greter M, Bogunovic M, Bellemare-Pelletier A, Frenette PS, Randolph GJ, Turley SJ, Merad M. Deciphering the transcriptional network of the dendritic cell lineage. Nature Immunology 2012 Sep; 13(9).
Mullokandov G *, Baccarini A *, Ruzo A *, Jayaprakash AD, Tung N, Israelow B, Evans MJ, Sachidanandam R, Brown BD. High-throughput assessment of microRNA activity and function using microRNA sensor and decoy libraries. Nature Methods 2012 Aug; 9(8).
Baccarini A, Chauhan H, Gardner TJ, Jayaprakash AD, Sachidanandam R, Brown BD. Kinetic analysis reveals the fate of a microRNA following target regulation in mammalian cells. Current Biology 2011 Mar; 21(5).
Chow A, Brown BD, Merad M. Studying the mononuclear phagocyte system in the molecular age. Nature Reviews Immunology 2011 Nov; 11(11).
Brown BD, Naldini L. Exploiting and antagonizing microRNA regulation for therapeutic and experimental applications. Nature Reviews Genetics 2009 Aug; 10(8).
Gentner B, Schira G, Giustacchini A, Amendola M, Brown BD, Ponzoni M, Naldini L. Stable knockdown of microRNA in vivo by lentiviral vectors. Nature Methods 2009 Jan; 6(1): 63-66.
Brown BD, Gentner B, Cantore A, Colleoni S, Amendola M, Zingale A, Baccarini A, Lazzari G, Galli C, Naldini L. Endogenous microRNA can be broadly exploited to regulate transgene expression according to tissue, lineage and differentiation state. Nature Biotechnology 2007 Dec; 25(12): 1457-1467.
Brown BD, Cantore A, Annoni A, Sergi LS, Lombardo A, Della Valle P, D'Angelo A, Naldini L, Galli C, Naldini L. A microRNA-regulated lentiviral vector mediates stable correction of hemophilia B mice. Blood 2007 Aug; 110(13): 4144-4152.
Brown BD, Sitia G, Annoni A, Hauben E, Sergi LS, Zingale A, Roncarolo MG, Guidotti L, Naldini L. In vivo administration of lentiviral vectors triggers a type I interferon response that restricts hepatocyte gene transfer and promotes vector clearance. Blood 2007 April; 109(7): 2797-2805.
Brown BD, Venneri MA, Zingale A, Sergi Sergi L, Naldini L. Endogenous microRNA regulation suppresses transgene expression in hematopoietic lineages and enables stable gene transfer. Nature Medicine 2006 May; 12(5): 585-591.
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