Gene Expressions, Human Genetics and Genetic Disorders, Migration, Schizophrenia, Stem Cells, Synaptogenesis
Clinical Research Education Program [CLR], Developmental and Stem Cell Biology [DSCB], Genetics and Genomic Sciences [GGS], Neuroscience [NEU]
BSc, University of Calgary
PhD, Harvard University
, Salk Institute for Biological Sciences
New York Stem Cell Foundation
NIH Biobehavioral Research Awards for Innovative New Scientists
Schizophrenia (SZ) is a debilitating psychiatric disorder. While its characteristic symptoms generally appear late in adolescence, SZ is thought to be a neurodevelopmental condition, often predated by a prodromal period that can appear in early childhood. Though postmortem studies of SZ brain tissue typically describe defects in mature neurons, such as reduced neuronal size and spine density in the prefrontal cortex and hippocampus, abnormalities of neuronal organization, particularly in the cortex, have also been reported. Due in part to the lack of live patient material for study, the cellular and molecular mechanisms of disease initiation and progression remain unknown. Though aberrant migration of human neural progenitor cells (NPCs) and reduced connectivity of human neurons has been hypothesized to contribute to disease initiation, neither mechanism is understood in live human neurons.
Through clinical collaborations, we have obtained skin samples from well-characterized cohorts of children and adults with SZ as well as samples from healthy controls. Having reprogrammed these skin cells into human induced pluripotent stem cells (hiPSCs) and directed these hiPSCs to undergo neural differentiation, we can generate near limitless quantities of live healthy and SZ NPCs and neurons. By identifying differences between healthy and diseased neurons, we hope to elucidate the mechanisms that result in SZ and to screen for new drugs with which to reverse the cellular defects contributing to disease.
Visit our website at: http://icahn.mssm.edu/research/labs/brennand-laboratory
Mertens J, Wang QW, Kim Y, Yu DX, Pham S, Yang B, Zheng Y, Diffenderfer KE, Zhang J, Soltani S, Eames T, Schafer ST, Boyer L, Marchetto MC, Nurnberger JI, Calabrese JR, Ødegaard KJ, McCarthy MJ, Zandi PP, Alba M, Nievergelt CM, Mi S, Brennand KJ, Kelsoe JR, Gage FH, Yao J. Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. Nature 2015 Nov; 527(7576).
Topol A, Tran NN, Brennand KJ. A guide to generating and using hiPSC derived NPCs for the study of neurological diseases. Journal of visualized experiments : JoVE 2015;(96).
Topol A, Zhu S, Tran N, Simone A, Fang G, Brennand KJ. Altered WNT Signaling in Human Induced Pluripotent Stem Cell Neural Progenitor Cells Derived from Four Schizophrenia Patients. Biological psychiatry 2015 Sep; 78(6).
Hartley BJ, Tran N, Ladran I, Reggio K, Brennand KJ. Dopaminergic differentiation of schizophrenia hiPSCs. Molecular psychiatry 2015 May; 20(5).
Hook V, Brennand KJ, Kim Y, Toneff T, Funkelstein L, Lee KC, Ziegler M, Gage FH. Human iPSC neurons display activity-dependent neurotransmitter secretion: aberrant catecholamine levels in schizophrenia neurons. Stem cell reports 2014 Oct; 3(4).
Brennand K, Savas JN, Kim Y, Tran N, Simone A, Hashimoto-Torii K, Beaumont KG, Kim HJ, Topol A, Ladran I, Abdelrahim M, Matikainen-Ankney B, Chao SH, Mrksich M, Rakic P, Fang G, Zhang B, Yates JR, Gage FH. Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia. Molecular psychiatry 2014 Apr;.
McConnell MJ, Lindberg MR, Brennand KJ, Piper JC, Voet T, Cowing-Zitron C, Shumilina S, Lasken RS, Vermeesch JR, Hall IM, Gage FH. Mosaic copy number variation in human neurons. Science (New York, N.Y.) 2013 Nov; 342(6158).
Hashimoto-Torii K, Torii M, Fujimoto M, Nakai A, El Fatimy R, Mezger V, Ju MJ, Ishii S, Chao SH, Brennand KJ, Gage FH, Rakic P. Roles of heat shock factor 1 in neuronal response to fetal environmental risks and its relevance to brain disorders. Neuron 2014 May; 82(3).
Yu DX, Di Giorgio FP, Yao J, Marchetto MC, Brennand K, Wright R, Mei A, McHenry L, Lisuk D, Grasmick JM, Silberman P, Silberman G, Jappelli R, Gage FH. Modeling hippocampal neurogenesis using human pluripotent stem cells. Stem cell reports 2014 Mar; 2(3).
Brennand KJ, Simone A, Jou J, Gelboin-Burkhart C, Tran N, Sangar S, Li Y, Mu Y, Chen G, Yu D, McCarthy S, Sebat J, Gage FH. Modelling schizophrenia using human induced pluripotent stem cells. Nature 2011 May; 473(7346): 221-225.
Brennand KJ. Inducing cellular aging: enabling neurodegeneration-in-a-dish. Cell stem cell 2013 Dec; 13(6).
Brennand KJ, Landek-Salgado MA, Sawa A. Modeling Heterogeneous Patients With a Clinical Diagnosis of Schizophrenia With Induced Pluripotent Stem Cells. Biological psychiatry 2014 Jun; 75(12).
Tran NN, Ladran IG, Brennand KJ. Modeling schizophrenia using induced pluripotent stem cell-derived and fibroblast-induced neurons. Schizophrenia bulletin 2013 Jan; 39(1).
Ladran I, Tran N, Topol A, Brennand KJ. Neural stem and progenitor cells in health and disease. Wiley interdisciplinary reviews. Systems biology and medicine; 5(6).
Brennand KJ, Simone A, Tran N, Gage FH. Modeling psychiatric disorders at the cellular and network levels. Molecular psychiatry 2012 Apr;.
Kim JE, O'Sullivan ML, Sanchez CA, Hwang M, Israel MA, Brennand K, Deerinck TJ, Goldstein LS, Gage FH, Ellisman MH, Ghosh A. Investigating Synapse Formation and Function Using Human ES and iPS Cell-derived Neurons. PNAS 2011; 108(7): 3005-3010.
Ruiz S, Brennand K, Panopoulos AD, Herrerías A, Gage FH, Izpisua-Belmonte JC. High-efficient generation of induced pluripotent stem cells from human astrocytes. PloS One 2010; 5(12).
Stadtfeld M, Brennand K, Hochedlinger K. Reprogramming of pancreatic beta cells into induced pluripotent stem cells. Current Biology 2008; 18(12): 890-894.
Brennand K, Huangfu D, Melton D. All β-cells contribute equally to pancreatic growth and maintenance. PLoS Biology 2007; 5(7): 1520-1529.
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