Stem cell functional models
We are each unique, comprised of distinct genetic, epigenetic and environmental risk factors that predispose us to some diseases and confer resilience to others. As expanding genetic studies increasingly demonstrate that both rare variants of large effect and common variants of small effect contribute to a variety of neuropsychiatric disorders, it becomes increasing critical that we unravel how these risk factors interact within and between the diverse cell types populating the brain. While mouse models are uniquely suited for demonstrating how aberrant function of single gene products contribute to aberrant circuit function and behavior, genetic studies of penetrance and complex gene interactions are nearly impossible to address using inbred mouse lines. Similarly, the lack of human post-mortem tissue, coupled with the inability to conduct functional validations on human cells, has to date left us with a very limited understanding of how rare and common variants impact gene expression or cellular function. By developing a human induced pluripotent stem cell (hiPSC)-based model for the study of predisposition to neuropsychiatric disease, we have established a new mechanism by which to systematically test the impact of causal variants in human cells. The future of psychiatry must be towards a model of precision medicine, whereby how the patient’s genetic variants, and the many interactions between them, impact disease course and treatment response is carefully considered before the prescription of any pills
The Brennand laboratory integrates stem cell approaches and CRISPR-based genomic and epigenomic editing to functionally resolve how genetic variants, as well as the interactions between variants and cell types, impact cellular function and underly risk to neuropsychiatric disease.
- Hartley BJ, Tran N, Ladran I, Reggio K, Brennand KJ. 2015. Dopaminergic differentiation of schizophrenia hiPSCs. Molecular Psychiatry. [PubMed]
- Topol A, Tran N, Brennand KJ. 2014. A guide to generating and using hiPSC derived NPCs for the study of neurological diseases. JOVE.
- Roussos P, Mitchell AC, Voloudakis G, Fullard JF, Pothula VM, Tsang J, Stahl EA, Georgakopoulos A, Ruderfer DM, Charney A, Okada Y, Siminovitch KA, Worthington J, Padyukov L, Klareskog L, Gregersen PK, Plenge RM , Raychaudhuri S , Fromer M, Purcell SM, Brennand KJ, Robakis NK, Schadt EE, Akbarian S, Sklar P. 2014. A role for non-coding variation in schizophrenia. [PubMed] Cell Reports. Nov 20;9(4):1417-29.
- Hook V, Brennand KJ, Kim Y-S, Toneff T, Funkelstein L, Lee K, Ziegler M, Gage FH. 2013. Regulation of Catecholamine Neurotransmitters Secreted in Schizophrenia Modeled by Human Induced Pluripotent Stem Cell Neurons. [PubMed] Stem Cell Reports. DOI: 10.1016/j.stemcr.2014.08.001. [Epub ahead of print]
- Hashimoto-Torii K, Torii M, Ju M, Fujimoto M, Nakai A, Fatimy RE, Mezger V, Chao J, Brennand KJ, Gage FH and Rakic P. 2014. Heat Shock Factor 1 is an Intersection between Genetic and Prenatal Environmental risk factors for Neuropsychiatric Disorders. Neuron.
- Brennand KJ*, Silvas J, Kim, Y, Tran N, Simone A, Hashimoto-Torii K, Beaumont K, Kim H-J, Topol A, Ladran I, Abdelrahim M, Matikainen-Ankney B, Chao S-h, Mrksich M, Rakic P, Fang G, Zhang B, Yates J, Gage FH*. 2014. Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia. [PubMed] Molecular Psychiatry. 1 April 2014; doi:10.1038/mp.2014.22. [Epub ahead of print]
- McConnell MJ, Lindberg MR, Brennand KJ, Piper J, Voet T, Cowing-Zitron C, Shumilina S, Lasken RS, Vermeesch J, Hall IM, and Gage FH. 2013. Mosaic Copy Number Variation in Human Neurons. [PubMed] Science.342(6158): 632-637. PMCID: 24179226.
- 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. 2011. Modeling Schizophrenia Using hiPSC Neurons. [PubMed] Nature. 473(7346): 221-225. PMID: 21490598. Comment in Cell Stem Cell: Buxbaum JD, Sklar P. 2011. Human induced pluripotent stem cells: a new model for schizophrenia? [PubMed] Cell Stem Cell. 8(5):461-462.Comment in Nat Rev Neuro Neurosci.: Welberg L. 2011. Stem Cells: Zooming in on schizophrenia. [PubMed] 12(6):308-309.
Reviews and Chapters
- Schadt E, Buchanan S, Brennand KJ, Merchant KM. 2014. Evolving towards a human-cell based and multiscale approach to drug discovery for CNS disorders. [PubMed] Frontiers in Neuroscience. In press
- Brennand KJ. 2013. Inducing Cellular Aging: Enabling Neurodegeneration-in-a-Dish. [PubMed] Cell Stem Cell. 2013 Dec 5;13(6):635-6. doi: 10.1016/j.stem.2013.11.017.
- Brennand KJ*, Landek-Salgado MA, and Sawa A. 2013. Modeling heterogeneous patients with schizophrenia using cell-based models. [PubMed] Biological Psychiatry. 2013 Nov 15. pii: S0006-3223(13)01000-7. doi: 10.1016/j.biopsych.2013.10.025. [Epub ahead of print]
- Ladran IG, Tran NN, Topol A, Brennand KJ. 2013. Neural stem/progenitor cells in health and disease. [PubMed] WIRE Systems Biology and Medicine. Wiley Interdiscip Rev Syst Biol Med. 2013 Sep 20. doi: 10.1002/wsbm.1239. [Epub ahead of print]
Using Stem Cells to Model Disease – Cell Press Webinar, 2013
Approach modeling of Alzheimer’s disease, Schizophrenia and Neurodegenerative disorders using patient-derived iPSCs, and to learn how these approaches could be applicable to modeling complex diseases. Podcast.
The Black Family Stem Cell Institute: Pushing Against the Unknown
Induced Pluripotent Stem Cells
Stem Cell on the Mesa, 2009. Podcast
Presenting the Future. 2016.
The Friedman Brain Institute: Conquering Brain Disease
Gallery – Scientific Images
I am looking to hire a post-doctoral scientist with experience in molecular biology and stem cell biology who is willing to generate and target key schizophrenia genes using state-of-the-art CRISPR-based methods. The goal will be to compare synaptic morphology and neuronal function between precise isogenic lines. Email CV.