个人简介
Dr. Bryan Heit was born and educated in Calgary where he developed an interest in research following a undergraduate research project in the laboratory of Dr. Paul Kubes. Here, Bryan began researching the role of phagocytes such as neutrophils in inflammatory responses. In 2001 This undergraduate project morphed into a PhD project in which Bryan elucidated the signalling pathways used by neutrophils to sort through the multitude of inflammatory mediators released in the vicinity of an infection such that the neutrophils are able to migrate to and destroy the invading pathogen. Bryan published 13 papers over the course of this project, and ultimately received the Governor Generals Gold Medal for Academic Achievement – Canada’s highest academic award – for this work.
In 2008 Bryan moved to Toronto, to pursue a post-doctorate in the laboratory of Dr. Sergio Grinstein. Here, Bryan studied a variety of topics including the molecular pathways regulating programmed cell death (apoptosis), phagocyte maturation and the survival of pathogens within phagocytes, and elucidated the signalling mechanisms used by CD36 – a receptor used to phagocytose malaria, tuberculosis and oxidized low-density lipoprotein (“bad” cholesterol). During this time Bryan developed significant expertise in live-cell and super-resolution microscopy; an interest which continues to this day and forms the foundation of much of his research.
In 2011 Bryan took up his first faculty position at the University of Western Ontario. Here, Bryan began studies assessing the mechanisms used by phagocytes for the removal of apoptotic cells, with a focus on how failures in these processes lead to diseases such as atherosclerosis. In addition, Dr. Heit continues his research into general phagocyte biology, phagocyte membrane biophysics, pathogen-phagocyte interactions and development of next-generation microscopy methods and analytical routines.
研究领域
Apoptosis, the controlled demolition of old, unneeded, infected or damaged cells, is fundamental to homeostasis and immunity. Each day billions of cells in our body undergo apoptosis, wherein the cellular contents of dying cells are degraded and packaged into membrane bound vesicles termed apoptotic bodies. Apoptotic bodies serve a dual purpose: they prevent the spillage of cellular contents into the extracellular milieu, while simultaneously packaging cell contents into particles small enough to be internalized by professional phagocytes.
The clearance of apoptotic bodies by phagocytes – termed efferocytosis – is required for tissue homeostasis, with failure to clear these particles leading to inflammation, autoimmunity and neurodegenerative diseases. If not cleared promptly, apoptotic bodies rupture and release their contents in a process termed secondary necrosis. Because these intracellular contents include pro-inflammatory substances such as nucleotides (ATP, UTP), secondary necrosis promotes inflammation. Indeed, the defective removal of apoptotic cells is an initiating event in inflammatory disorders such as atherosclerosis. While it is unclear if secondary necrosis drives autoimmunity, it is well established that the presentation of antigens derived from apoptotic cells plays a central role in maintaining self-tolerance, with failures in this system leading to autoimmunity. The regulation of apoptosis and the subsequent clearance of apoptotic cells also contributes to immunity against infectious agents such as viruses and intracellular bacteria. Efferocytosis of apoptotic bodies released by infected cells allows for the processing and presentation of intracellular pathogen-derived antigens by professional phagocytes. These phagocytes then transport these normally sequestered antigens to lymphatic tissues, where the antigens are the presented on MHC II, thus driving the formation of adaptive immunity.
Despite the obvious importance of efferocytosis, little is known about the process itself. Efferocytosis is a three step process, consisting of an initial recognition of the apoptotic body, internalization of the apoptotic body by a phagocyte, and finally, destruction of the apoptotic body. Research in the Heit lab focuses on the signalling which regulates these processes, with a focus on the receptors that bind apoptotic bodies and the signalling these receptors induce.
近期论文
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Yin C, Kim Y, Argintaru D, Heit B. Rab17 mediates differential antigen sorting following efferocytosis and phagocytosis. Cell Death and Disease. 2016 Dec 22;7(12):e2529. [PubMed][Article]
Dirk BS, Pawlak EN, Johnson AL, Van Nynatten LR, Jacob RA, Heit B, Dikeakos JD. HIV-1 Nef sequesters MHC-I intracellularly by targeting early stages of endocytosis and recycling. Scientific Reports. 2016 Nov 14;6:37021. [Pubmed] [Article]
Evans AL, Blackburn JW, Yin C, Heit B. Quantitative Efferocytosis Assays. Methods Mol Biol. 2017;1519:25-41. [PubMed] [Article].
Goiko M, de Bruyn JR, Heit B. Short-Lived Cages Restrict Protein Diffusion in the Plasma Membrane. Scientific Reports. 2016 Oct 11;6:34987. [PubMed] [Article]
Winick-Ng W, Caetano FA, Winick-Ng J, Morey TM, Heit B, Rylett RJ. 82-kDa choline acetyltransferase and SATB1 localize to β-amyloid induced matrix attachment regions. Scientific Reports. 2016 Apr 7;6:23914. [PubMed] [Article]
Dunn HA, Chahal HS, Caetano FA, Holmes KD, Yuan GY, Parikh R, Heit B, Ferguson SS. PSD-95 regulates CRFR1 localization, trafficking and β-arrestin2 recruitment. Cellular Signalling. 2016 May;28(5):531-40. [PubMed] [Aritcle]
Caetano FA, Dirk BS, Tam JH, Cavanagh PC, Goiko M, Ferguson SS, Pasternak SH, Dikeakos JD, de Bruyn JR, Heit B. MIiSR: Molecular Interactions in Super-Resolution Imaging Enables the Analysis of Protein Interactions, Dynamics and Formation of Multi-protein Structures. PLoS Computational Biology. 2015 Dec 11;11(12):e1004634. [Pubmed] [Article]
Armstrong SM, Sugiyama MG, Fung KY, Gao Y, Wang C, Levy AS, Azizi P, Roufaiel M, Zhu SN, Neculai D, Yin C, Bolz SS, Seidah NG, Cybulsky MI, Heit B, Lee WL. A novel assay uncovers an unexpected role for SR-BI in LDL transcytosis. Cardiovascular Research. 2015 Nov 1;108(2):268-77. [Pubmed] [Article]
Flannagan RS, Heit B, Heinrichs DE. Intracellular replication of Staphylococcus aureus in mature phagolysosomes in macrophages precedes host cell death, and bacterial escape and dissemination. Cellular Microbiology. 2015 Sep 26. [Pubmed] [Article]
Hossain M, Qadri SM, Xu N, Su Y, Cayabyab FS, Heit B, Liu L. Endothelial LSP1 Modulates Extravascular Neutrophil Chemotaxis by Regulating Nonhematopoietic Vascular PECAM-1 Expression. Journal of Immunology. 2015 Sep 1;195(5):2408-16. PMID: 26238489. [Pubmed] [Article]
Dirk BS, Heit B, Dikeakos JD. Visualizing Interactions Between HIV-1 Nef and Host Cellular Proteins Using Ground-State Depletion Microscopy. AIDS Research and Human Retroviruses. 2015 Jul;31(7):671-2. [Pubmed] [Article]
Pillon NJ, Azizi PM, Li YE, Liu J, Wang C, Chan KL, Hopperton KE, Bazinet RP, Heit B, Bilan PJ, Lee WL, Klip A. Palmitate-induced inflammatory pathways in human adipose microvascular endothelial cells promote monocyte adhesion and impair insulin transcytosis. American Journal of Physiololgy – Endocrinology and Metabolism. 2015 Jul [Pubmed] [Article]
Azizi PM, Zyla RE, Guan S, Wang C, Liu J, Bolz SS, Heit B, Klip A, Lee WL. Clathrin-dependent entry and vesicle-mediated exocytosis define insulin transcytosis across microvascular endothelial cells. Molecular Biology of the Cell. 2015 Feb 15;26(4):740-50. [Pubmed] [Article]
Wong HS, Jaumouillé V, Heit B, Doodnauth SA, Patel S, Huang YW, Grinstein S, Robinson LA. Cytoskeletal confinement of CX3CL1 limits its susceptibility to proteolytic cleavage by ADAM10. Molecular Biology of the Cell. 2014 Dec 1;25(24):3884-99. [Pubmed] [Article]
Heit B, Kim H, Cosío G, Castaño D, Collins R, Lowell CA, Kain KC, Trimble WS, Grinstein S. Multimolecular signaling complexes enable Syk-mediated signaling of CD36 internalization.. Developmental Cell. 2013 Feb 25;24(4):372-83 [PubMed] [Article]
Heit B, Yeung T, Grinstein S. Changes in mitochondrial surface charge mediate recruitment of signaling molecules during apoptosis. Am J Physiol Cell Physiol. 2011 Jan;300(1):C33-41. Epub 2010 Oct 6. [PubMed] [Article]
Yeung T, Heit B, Dubuisson JF, Fairn GD, Chiu B, Inman R, Kapus A, Swanson M, Grinstein S. Contribution of phosphatidylserine to membrane surface charge and protein targeting during phagosome maturation. J Cell Biol. 2009 Jun 1;185(5):917-28. [PubMed] [PubMed Central] [Article]
Phillipson M, Heit B, Parsons SA, Petri B, Mullaly SC, Colarusso P, Gower RM, Neely G, Simon SI, Kubes P. Vav1 is essential for mechanotactic crawling and migration ofneutrophils out of the inflamed microvasculature. J Immunol. 2009 Jun 1;182(11):6870-8. [PubMed] [Article]
Heit B, Robbins SM, Downey CM, Guan Z, Colarusso P, Miller BJ, Jirik FR, Kubes P. PTEN functions to ‘prioritize’ chemotactic cues and prevent ‘distraction’ in migrating neutrophils. Nat Immunol. 2008 Jul;9(7):743-52. Epub 2008 Jun 8. [PubMed] [Article] [F1000]
Heit B, Liu L, Colarusso P, Puri KD, Kubes P. PI3K accelerates, but is not required for, neutrophil chemotaxis to fMLP. J Cell Sci. 2008 Jan 15;121(Pt 2):205-14. [PubMed] [Article]
Phillipson M, Heit B, Colarusso P, Liu L, Ballantyne CM, Kubes P. Intraluminal crawling of neutrophils to emigration sites: a molecularly distinct process from adhesion in the recruitment cascade. J Exp Med. 2006 Nov 27;203(12):2569-75. Epub 2006 Nov 20. [PubMed] [PubMed Central] [Article] [F1000]
Heit B, Jones G, Knight D, Antony JM, Gill MJ, Brown C, Power C, Kubes P. HIV and other lentiviral infections cause defects in neutrophil chemotaxis, recruitment, and cell structure: immunorestorative effects of granulocyte-macrophage colony-stimulating factor. J Immunol. 2006 Nov 1;177(9):6405-14. [PubMed] [Article]
Heit B, Colarusso P, Kubes P. Fundamentally different roles for LFA-1, Mac-1 and alpha4-integrin in neutrophil chemotaxis. J Cell Sci. 2005 Nov 15;118 (Pt 22):5205-20. Epub 2005 Oct 25. [PubMed] [Article]
Khan AI, Heit B, Andonegui G, Colarusso P, Kubes P. Lipopolysaccharide: a p38 MAPK-dependent disrupter of neutrophil chemotaxis. Microcirculation. 2005 Jul-Aug;12(5):421-32. [PubMed] [Article]
Khan AI, Kerfoot SM, Heit B, Liu L, Andonegui G, Ruffell B, Johnson P, Kubes P. Role of CD44 and hyaluronan in neutrophil recruitment. J Immunol. 2004 Dec 15;173(12):7594-601. [PubMed] [Article]
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