Brain Project: Ontario Brain Institute & Bioasis Technologies, Inc.
This is a group of reproduced information about the project that studies how the human brain works and how to best protect it and treat disorders of the brain and nervous system, which is a new global research wave as important as that of Human Genome Research Project.
The Bioasis Technologies, Inc. is in play leading role in Brain study project of Canada, and Prof. Elizabeth M. Simpson is a main researcher.
May 27, 2015, article Focus on Brain: $10M for breakthrough technologies to address unmet needs in neurosciences reports that Brain Canadaand the Ontario Brain Institute (OBI) award close to$8.5Mto six (6) multi-disciplinary and multi-provincial research teams across Canada to address unmet needs in neuroscience within their Focus on Brain strategic initiative. To this amount,$1.5Mis added from the various research entities involved as in-kind contributions. This exciting announcement was made today at the annual meeting of the Canadian Association for Neuroscience in the presence ofInez Jabalpurwala, President and CEO ofBrain Canada;Mario Chevrette, Vice President, Scientific Affairs of CQDM; andDonald Stuss, President and Scientific Director of OBI.
The six (6) awarded research teams will be led by Rob Hutchison from biOasis Technologies Inc. in Vancouver, Janusz Pawliszyn from the University of Waterloo, Elizabeth Simpson from the University of British Columbia, Jean-Paul Soucy from McGill University, Don van Meyel from the Research Institute-McGill University Health Centre and Nathan Yoganathan from KalGene Pharmaceuticals Inc. in Toronto.
Who we are: We are a provincially-funded, not-for-profit research centre maximizing the impact of neuroscience and establishing Ontario as a world leader in brain research, commercialization and care.
Our Vision: Ontario as a world leader in brain research, commercialization and care.
We realize this through convergent partnerships between researchers, clinicians, industry, patients, and their advocates to foster discovery and deliver innovative products and services that improve the lives of those living with brain disorders.
What we do: Our collaborative approach to research aims to:
1. Enhance the neuroscience research system
2. Grow the Ontario neurotechnology cluster
3. Improve brain health for Ontarians
Team Science
Our goal is to improve the lives of Ontarians living with a brain disorder. Our research either goes to commercialization or to impacting how people with brain disorders receive care. We create seamless connections between research discovery, patient care and commercialization. We do this by connecting researchers, patients, companies, and policy makers to form a learning healthcare system. These networks form what we call Integrated Discovery Programs.
Ontario Brain
Institute Announces
New President &
Scientific Director
Hugh MacKinnon, Chair of the
Ontario Brain Institute’s Board of
Directors, is delighted to announce
that after an extensive international
search, Dr. Tom Mikkelsen will join
OBI as President & Scientific Director.
Following a distinguished career in
the U.S. as one of the top neurooncologists
with the Henry Ford
Medical Group, Dr. Mikkelsen will
be returning to his native Canada
to drive the Ontario Brain Institute
forward as its new leader. Dr.
Mikkelsen received his MD from the
University of Calgary and completed
clinical training in neurology at the
Montreal Neurological Institute.
Following this, he did postdoctoral
training in tumour and molecular
biology at the Ludwig Institute for
Cancer Research in Montreal and
then in La Jolla, California.
Since
1992, he has led the brain tumour
program at Henry Ford Hospital and
was responsible for building the clinical
trials program and laboratory of
tumour biology. Together with other
scientists, he helped assemble the
Hermelin Brain Tumor Center, a leader
in the understanding of the genetics
of brain tumours and in the development
of treatments for brain
tumours.
As Co-Director, he participated
in the organization’s development
on many levels spanning from
face-to-face clinical care, to clinical
trials, and translational and bench
research.
In his new role, Dr. Mikkelsen will
spearhead OBI’s management team
to maximize the impact of neuroscience
and the position of Ontario
as a world leader in brain research,
commercialization and care.
Message From Dr. Tom Mikkelsen, President And Scientific Director Of OBI
Your brain is always changing. It is constantly processing information from your body and making sense of the world around you. And in doing so, your brain itself is changing. In fact it continues changing throughout your lifetime. You experience this change with every new skill you learn, and every old memory you forget. Neurogenesis, or the creation of new brain cells, is a primary driver of this change: cells are born then differentiate into a specific type of neuron, migrate to their destination in the brain, and then finally integrate into a new or existing network. As the new President and Scientific Director of the Ontario Brain Institute, I feel this is a fitting way to introduce myself to all of you.
I was born and schooled in Canada where I received an MD from the University of Calgary and then completed my clinical training in neurology at the Montreal Neurological Institute. Following this, I ‘differentiated’ as a post-doctoral fellow, training in tumour and molecular biology at the Ludwig Institute for Cancer Research in Montreal and then University of California San Diego in La Jolla California. I continued my ‘migration’, moving to Detroit to lead the Brain Tumour Program at Henry Ford Hospital and build the Hermelin Brain Tumor Center which became a leader in the understanding of the genetics of brain tumours and in the development of treatments for brain tumours.
Throughout my career as a neurologist and researcher, I have witnessed first-hand the value of taking a collaborative approach to science that engages patients and industry as part of the process. This approach to research is at the core of OBI and is why I am enthusiastic to ‘integrate’ into the role of President and Scientific Director. I am fortunate to be guided by the vision set in place by Dr. Donald Stuss and Mr. Joseph Rotman, the Founding President and Scientific Director and Founding Chairman of the Board, respectively. With OBI, I am excited to continue on this path and drive forward the research that will create better treatments and improve the quality of life for the nearly one million individuals in Ontario who currently live with a brain disorder.
Already, we are seeing early evidence of the research, economic, and health impacts arising from a collaborative approach to brain research and innovation.
One example stems from direct collaboration between researchers. Learn how two researchers, one who studies the aging brain and one who studies pre-term infants have found common ground and forged a collaboration across brain disorders at opposite ends of the lifespan. You can also read about other research updates from our five Integrated Discovery Programs.
Another example of a research impact relates to data sharing. OBI set up a system where researchers can share data, collaborate, and ultimately gain deeper insight into causes and mechanisms of brain disorders. Data shared through Brain-CODE, the OBI informatics and analytics platform, is creating a research database that is a valuable resource for those within the network, and outside of it. Read about a new partnership between OBI and the National Institute of Health that will advance autism research by allowing scientists in Canada and the US to link research data.
Brain research is central to OBI, and it is also our job to help it take the next step to yield economic and health outcomes. Learn how OBI has helped a spin-out company navigate the tricky terrain and integrate into the Ontario neurotech cluster. You can also read about how OBI has helped turn knowledge into action and used evidence to improve brain health.
As the ‘new neuron’ in the network I have to say that it is incredible to see what has been accomplished by OBI and its partners. I feel privileged to share these updates with you, and I invite you to follow our progress and share your comments on our blog or through social media.
Thank you all for your ongoing interest and support for OBI.
Delivery of therapeutics across the blood-brain barrier and into the brain has been the single greatest challenge to treating hundreds of common and rare neurological diseases, including brain cancers, neurodegenerative diseases and metabolic disorders
At Bioasis, we undertake this challenge by focusing on a single goal: revolutionizing science by transporting therapeutic payloads across the blood-brain barrier and into the brain. Bioasis has developed and is commercializing our proprietary brain delivery technology, the xB3 platform, to make life-saving drugs brain-penetrant and deliver those therapies at a therapeutically relevant dose.
The Blood-Brain Barrier Company
History
Upon acquiring research developed at the University of British Columbia (UBC) in 2007, Mr. Rob Hutchison founded Bioasis Technologies, Inc. in Vancouver, Canada. Bioasis became a publicly traded company in 2008 and trades on the TSX Venture Exchange under the symbol “BTI” and on the OTCQB under the symbol “BIOAF.”
Building upon the UBC work, Bioasis researchers created technology called the Transcend platform, capable of transporting therapeutics across the blood-brain barrier. Bioasis scientists then spent the last decade collaborating on research with leading pharmaceutical companies and academic institutions to further develop the Transcend-peptide platform. The platform is based on a human transport protein, melanotransferrin, which is found circulating in low levels in the blood. Preclinical studies have demonstrated that our platform technologies are independent of the transferrin receptor in their transport mechanism.
The Transcend-peptide platform will now be referred to as the xB3 platform and is part of the Bioasis patented portfolio that is revolutionizing therapeutic brain-drug delivery. Preclinical studies have demonstrated that the xB3 platform can transport molecules of varying sizes and types including monoclonal antibodies, enzymes, small molecules, small-interfering RNA (siRNA) and other types of gene therapies into the brain through a process called receptor-mediated transcytosis.
In April 2017, Mr. Hutchison was appointed chairman of the Bioasis Board of Directors, and Dr. Mark Day became president and chief executive officer of Bioasis. The company opened offices in Guilford, Connecticut, in September 2017 and continues to maintain its headquarters in Vancouver, Canada.
Delivering Hope
Our focus is to deliver hope to over 1.25 billion patients worldwide who suffer from hundreds of previously untreatable diseases and disorders of the central nervous system.
We know what our scientific advances can mean for a single patient — a second chance.
Elizabeth M. Simpson
Therapies for the brain and eye represent a major unmet need, and gene therapy is emerging as a real treatment option, with numerous clinical trials ongoing such as those for macular degeneration, and Alzheimer and Parkinson Disease.
The overall goal of my research is to develop gene-based therapies for diseases of the brain and eye. My approach is to use rAAV (recombinant adeno-associated virus) to deliver therapies to treat mouse models of human disease. Currently, we are mining the human genome for cell-type-specific promoters to use in viruses, and developing gene augmentation and genome editing (CRISPR/cas9) therapies focused on curing the congenital blindness aniridia.
Aniridia is a rare, congenital, panocular, eye disorder. Individuals with aniridia are typically born with low vision, and because there is no effective treatment, subsequently lose all vision. Thus, there is a therapeutic window available to prevent vision loss. Our short-term goal is to cure the mouse model of aniridia. Curing aniridia in mice will lay the conceptual and practical foundation upon which human gene therapy can be designed.
We still have only a cursory understanding of the 98% of the human genome that is non-coding. However, we do know that it contains large complex promoters. Understanding and harnessing this regulatory potential into “MiniPromoters” (small selected regions of human promoters), to drive gene expression in defined regions of the brain and eye, is an interest of Dr. Simpson. Such MiniPromoters have many applications for basic and clinical research, but the most demanding and exciting is gene therapy; a promising approach for diseases with unmet therapeutic needs.
Senior Scientist, Centre for Molecular Medicine and Therapeutics (CMMT) Scientist Level 3, British Columbia Children’s Hospital Research Professor, Department of Medical Genetics, UBC Associate Member, Department of Psychiatry, UBC Associate Member, Department of Ophthalmology & Visual Sciences, UBC
Simpson Lab Research Projects
The overall goal of my research is to develop gene-based therapies for diseases of the brain and eye. My approach is to use rAAV (recombinant adeno-associated virus) to deliver therapies to treat mouse models of human disease. Currently, we are mining the human genome for cell-type-specific promoters to use in viruses, and developing gene augmentation and genome editing (CRISPR/cas9) therapies focused on curing the congenital blindness aniridia.
GENE THERAPY FOR ANIRIDIA
Our goal is to develop an rAAV-based gene therapy for aniridia. Our experiments are the first towards rAAV-based gene therapy for aniridia in mouse.
Aniridia is a rare, congenital, panocular, eye disorder. Individuals with aniridia are typically born with low vision, and because there is no effective treatment, subsequently lose all vision. Thus, there is a therapeutic window available to prevent vision loss. Approximately 80% of individuals with aniridia are known to carry a mutation affecting one copy of the transcription factor PAX6 (paired box gene 6). Our long-term goal is to make gene therapy an option for patients with aniridia. Our short-term goal is to cure the mouse model of aniridia. Curing aniridia in mice will lay the conceptual and practical foundation upon which human gene therapy can be designed.
Gene therapy uses nucleic acids to alter cellular behavior and treat disease. After 25 years of research, the promise of gene therapy is being realized; currently there are 24 rAAV-based ocular clinical trials ongoing. The eye is an excellent organ for gene therapy because it is easily accessible. Currently we are taking a two-pronged approach to gene therapy for aniridia: augmentation gene therapy, and genome editing using CRISPR (clustered regularly interspaced short palindromic repeats) /cas9 (CRISPR-associated nuclease 9).
For augmentation gene therapy, we are delivering additional PAX6 encoded in rAAV directly to the mouse eye. Because PAX6 may need to be carefully regulated, we have designed “MiniPromoters” (small selected regions of human promoters) from the human PAX6 gene and tested them in the mouse eye (Hickmott et al., 2016 in revision). Two PAX6-MiniPromoters drove expression in three of the four cell types that express PAX6 in the adult mouse retina. Combined, they capture all four-cell types, making them potential tools for research, and PAX6-gene therapy for aniridia. Successfully using a transcription factor to treat aniridia will not only provide a treatment for this disorder, but further clear the path for other rare disorders, and for the first time open up many transcription factor diseases for gene therapy.
For genome-editing therapy, we are using the bacterial CRISPR/cas9 system. It will be delivered in rAAV to edit genomic DNA in vivo in a mouse model of aniridia. Thus, we will merge the safe and efficient access to a variety of cell types achieved by AAV, with the precision of CRISPR/cas9 editing. This base-pair substitution strategy would be applicable to 62–86% of classical aniridia patients. The final therapy would be “precision medicine”, in that a different CRISPR/cas9 gene-editing assay would be needed for each patient.
HUMAN MINIPROMOTERS FOR RESTRICTED EXPRESSION OF OCULAR AND BRAIN GENE THERAPY
We still have only a cursory understanding of the 98% of the human genome that is non-coding. However, we do know that it contains large complex promoters, often with regulatory modules dispersed throughout the gene. Understanding and harnessing this regulatory potential into “MiniPromoters” (small selected regions of human promoters), to drive gene expression in defined regions of the brain and eye, is an interest of Dr. Simpson and her colleagues. Such MiniPromoters have many applications for basic and clinical research, but the most demanding and exciting is gene therapy; a promising approach for diseases with unmet therapeutic needs. By being cell type specific, MiniPromoters are designed to increase gene therapy safety by reducing off-target side effects, while increasing efficacy by broadening the pallet of therapeutic proteins that can be safely delivered.
We have taken steps towards filling the need for MiniPromoters by developing a high-throughput pipeline that goes from genome-based bioinformatic design to rapid testing in vivo. For much of this work, therapeutically interesting Pleiades MiniPromoters, which were ~4 kb and previously tested in knock-in mice (de Leeuw et al., 2014), are being “cut down” to ~2.5 kb and tested in recombinant adeno-associated virus (rAAV); the virus of choice for gene therapy of the central nervous system. The data has shown that 16 of the 19 (84%) MiniPromoters recapitulated the expression pattern of their design source. This included expression of: Ple67 in brain raphe nuclei; Ple155 in Purkinje cells of the cerebellum, and retinal bipolar ON cells; Ple261 in endothelial cells of brain blood vessels; and Ple264 in retinal Müller glia. Overall, the methodology and the resulting MiniPromoters are important advances for basic and preclinical research, and may enable a paradigm shift in gene therapy.
Currently these genome studies to design MiniPromoters are being funded by Brain Canada/CQDM for a project entitled: “Human MiniPromoters for Restricted Expression of Ocular Gene Therapy”. The main deliverable is a toolkit of human MiniPromoters with restricted expression suitable for ocular gene therapy. The toolkit will include 18 MiniPromoters, fully characterized in mouse for overall CNS, and detailed eye, expression. In total, 48 viruses carrying 30 MiniPromoters will be studied; with an expected success rate of 60%. The three most therapeutically promising will also be fully characterized in the monkey eye. Their most avant garde MiniPromoter recently enabled a previously unsuccessful rAAV gene therapy to restore visual function in a mouse model of congenital night blindness (Scalabrino et al., 2015). Thus, these MiniPromoter tools will be positioned for investment by biopharmaceutical companies interested in delivering therapeutic molecules to the eye.
These tools are being distributed worldwide via The Jackson Laboratory (75 mouse strains) and Addgene (366 plasmids, 260 requests).
MAJOR ACHIEVEMENTS & PUBLICATIONS
As part of a collaborative team, Dr. Simpson’s laboratory restored visual function in a mouse model of complete congenital stationary night blindness (Scalabrino et al., 2015). – 2015
Genome British Columbia Award for Scientific Excellence (LifeSciences BC) – 2014
Canada Research Chair, Tier II, Genetics & Behaviour – 2001-2010
AAV-Compatible MiniPromoters for Restricted Expression in the Brain and Eye. de Leeuw, C.N.d., Korecki, A.J., Berry, G.E., Hickmott, J.W., Lam, S.L., Lengyell, T.C., Bonaguro, R.J., Borretta, L., Chopra, V., Chou, A.Y., D’Souza, C.A., Kaspieva, O., Laprise, S., McInerny, S.C., Portales-Casamar, E., Swanson-Newman, M.I., Wong, K., Yang, G.S., Zhoua, M., Jones, S.J.M., Holt, R.A., Asokan, A., Goldowitz, D., Wasserman, W.W., and Simpson, E.M. (2016). Molecular Brain, 9(1):52, Impact Factor 3.617, Cited 3, PMID 27164903.
PAX6 MiniPromoter Drive Restricted Expression from rAAV in the Adult Mouse Retina. Hickmott, J., Chen, C.-y., Arenillas, D.J., Korecki, A.J., Lam, S.L., Molday, L.L., Bonaguro, R.J., Zhou, M., Chou, A.Y., Mathelier, A., Boye, S.L., Hauswirth, W.W., Molday, R.S., Wasserman, W.W., and Simpson, E.M. (2016). Molecular Therapy – Methods & Clinical Development, 3: 16051, Impact Factor Not Yet Assigned, PMID 27556059.
Co-activator candidate interactions for the orphan nuclear receptor NR2E1. Corso-Díaz, X., de Leeuw, C., Alonso, V., Melchers, D., Wong, B.K., Houtman, R., and Simpson, E.M. (2016). BMC Genomics, 17(1): 832, Impact Factor 3.867, PMID 27782803.
Elizabeth Simpson Publications
Connell, M, Chen, H, Jiang, J, Kuan, CW, Fotovati, A, Chu, TL et al.. HMMR acts in the PLK1-dependent spindle positioning pathway and supports neural development. Elife. 2017;6 :. doi: 10.7554/eLife.28672. PubMed PMID:28994651 .
Corso-Díaz, X, de Leeuw, CN, Alonso, V, Melchers, D, Wong, BK, Houtman, R et al.. Co-activator candidate interactions for orphan nuclear receptor NR2E1. BMC Genomics. 2016;17 (1):832. doi: 10.1186/s12864-016-3173-5. PubMed PMID:27782803 PubMed Central PMC5080790.
Hickmott, JW, Chen, CY, Arenillas, DJ, Korecki, AJ, Lam, SL, Molday, LL et al.. PAX6 MiniPromoters drive restricted expression from rAAV in the adult mouse retina. Mol Ther Methods Clin Dev. 2016;3 :16051. doi: 10.1038/mtm.2016.51. PubMed PMID:27556059 PubMed Central PMC4980111.
de Leeuw, CN, Korecki, AJ, Berry, GE, Hickmott, JW, Lam, SL, Lengyell, TC et al.. rAAV-compatible MiniPromoters for restricted expression in the brain and eye. Mol Brain. 2016;9 (1):52. doi: 10.1186/s13041-016-0232-4. PubMed PMID:27164903 PubMed Central PMC4862195.
Scalabrino, ML, Boye, SL, Fransen, KM, Noel, JM, Dyka, FM, Min, SH et al.. Intravitreal delivery of a novel AAV vector targets ON bipolar cells and restores visual function in a mouse model of complete congenital stationary night blindness. Hum. Mol. Genet. 2015;24 (21):6229-39. doi: 10.1093/hmg/ddv341. PubMed PMID:26310623PubMed Central PMC4612567.
Schmouth, JF, Arenillas, D, Corso-Díaz, X, Xie, YY, Bohacec, S, Banks, KG et al.. Combined serial analysis of gene expression and transcription factor binding site prediction identifies novel-candidate-target genes of Nr2e1 in neocortex development. BMC Genomics. 2015;16 :545. doi: 10.1186/s12864-015-1770-3. PubMed PMID:26204903 PubMed Central PMC4512088.
Corso-Díaz, X, Simpson, EM. Nr2e1 regulates retinal lamination and the development of Müller glia, S-cones, and glycineric amacrine cells during retinogenesis. Mol Brain. 2015;8 :37. doi: 10.1186/s13041-015-0126-x. PubMed PMID:26092486 PubMed Central PMC4475312.
de Leeuw, CN, Dyka, FM, Boye, SL, Laprise, S, Zhou, M, Chou, AY et al.. Targeted CNS Delivery Using Human MiniPromoters and Demonstrated Compatibility with Adeno-Associated Viral Vectors. Mol Ther Methods Clin Dev. 2014;1 :5. doi: 10.1038/mtm.2013.5. PubMed PMID:24761428 PubMed Central PMC3992516.
Schmouth, JF, Castellarin, M, Laprise, S, Banks, KG, Bonaguro, RJ, McInerny, SC et al.. Non-coding-regulatory regions of human brain genes delineated by bacterial artificial chromosome knock-in mice. BMC Biol. 2013;11 :106. doi: 10.1186/1741-7007-11-106. PubMed PMID:24124870 PubMed Central PMC4015596.
Corso-Díaz, X, Borrie, AE, Bonaguro, R, Schuetz, JM, Rosenberg, T, Jensen, H et al.. Absence of NR2E1 mutations in patients with aniridia. Mol. Vis. 2012;18 :2770-82. . PubMed PMID:23213277 PubMed Central PMC3513187.
Yang, C, McLeod, AJ, Cotton, AM, de Leeuw, CN, Laprise, S, Banks, KG et al.. Targeting of >1.5 Mb of human DNA into the mouse X chromosome reveals presence of cis-acting regulators of epigenetic silencing. Genetics. 2012;192 (4):1281-93. doi: 10.1534/genetics.112.143743. PubMed PMID:23023002 PubMed Central PMC3512139.
Bradley, A, Anastassiadis, K, Ayadi, A, Battey, JF, Bell, C, Birling, MC et al.. The mammalian gene function resource: the International Knockout Mouse Consortium. Mamm. Genome. 2012;23 (9-10):580-6. doi: 10.1007/s00335-012-9422-2. PubMed PMID:22968824 PubMed Central PMC3463800.
Murray, SA, Eppig, JT, Smedley, D, Simpson, EM, Rosenthal, N. Beyond knockouts: cre resources for conditional mutagenesis. Mamm. Genome. 2012;23 (9-10):587-99. doi: 10.1007/s00335-012-9430-2. PubMed PMID:22926223PubMed Central PMC3655717.
Yusuf, D, Butland, SL, Swanson, MI, Bolotin, E, Ticoll, A, Cheung, WA et al.. The transcription factor encyclopedia. Genome Biol. 2012;13 (3):R24. doi: 10.1186/gb-2012-13-3-r24. PubMed PMID:22458515 PubMed Central PMC3439975.
Schmouth, JF, Bonaguro, RJ, Corso-Diaz, X, Simpson, EM. Modelling human regulatory variation in mouse: finding the function in genome-wide association studies and whole-genome sequencing. PLoS Genet. 2012;8 (3):e1002544. doi: 10.1371/journal.pgen.1002544. PubMed PMID:22396661 PubMed Central PMC3291530.
Schmouth, JF, Banks, KG, Mathelier, A, Gregory-Evans, CY, Castellarin, M, Holt, RA et al.. Retina restored and brain abnormalities ameliorated by single-copy knock-in of human NR2E1 in null mice. Mol. Cell. Biol. 2012;32 (7):1296-311. doi: 10.1128/MCB.06016-11. PubMed PMID:22290436 PubMed Central PMC3302440.
Aubrecht, J, Goad, ME, Czopik, AK, Lerner, CP, Johnson, KA, Simpson, EM et al.. A high G418-resistant neo(R) transgenic mouse and mouse embryonic fibroblast (MEF) feeder layers for cytotoxicity and gene targeting in vivoand in vitro. Drug Chem Toxicol. 2011;34 (4):433-9. doi: 10.3109/01480545.2010.544316. PubMed PMID:21740348.
Portales-Casamar, E, Swanson, DJ, Liu, L, de Leeuw, CN, Banks, KG, Ho Sui, SJ et al.. A regulatory toolbox of MiniPromoters to drive selective expression in the brain. Proc. Natl. Acad. Sci. U.S.A. 2010;107 (38):16589-94. doi: 10.1073/pnas.1009158107. PubMed PMID:20807748 PubMed Central PMC2944712.
Wong, BK, Hossain, SM, Trinh, E, Ottmann, GA, Budaghzadeh, S, Zheng, QY et al.. Hyperactivity, startle reactivity and cell-proliferation deficits are resistant to chronic lithium treatment in adult Nr2e1(frc/frc) mice. Genes Brain Behav. 2010;9 (7):681-94. doi: 10.1111/j.1601-183X.2010.00602.x. PubMed PMID:20497236 PubMed Central PMC3292041.
Milisavljevic, M, Hearty, T, Wong, TY, Portales-Casamar, E, Simpson, EM, Wasserman, WW et al.. Laboratory Animal Management Assistant (LAMA): a LIMS for active research colonies. Mamm. Genome. 2010;21 (5-6):224-30. doi: 10.1007/s00335-010-9258-6. PubMed PMID:20411264 PubMed Central PMC5047758.
Mazarei, G, Neal, SJ, Becanovic, K, Luthi-Carter, R, Simpson, EM, Leavitt, BR et al.. Expression analysis of novel striatal-enriched genes in Huntington disease. Hum. Mol. Genet. 2010;19 (4):609-22. doi: 10.1093/hmg/ddp527. PubMed PMID:19934114 PubMed Central PMC2807369.
Van Raamsdonk, CD, Bezrookove, V, Green, G, Bauer, J, Gaugler, L, O'Brien, JM et al.. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature. 2009;457 (7229):599-602. doi: 10.1038/nature07586. PubMed PMID:19078957 PubMed Central PMC2696133.
Yang, GS, Banks, KG, Bonaguro, RJ, Wilson, G, Dreolini, L, de Leeuw, CN et al.. Next generation tools for high-throughput promoter and expression analysis employing single-copy knock-ins at the Hprt1 locus. Genomics. 2009;93 (3):196-204. doi: 10.1016/j.ygeno.2008.09.014. PubMed PMID:18950699 .
D'Souza, CA, Chopra, V, Varhol, R, Xie, YY, Bohacec, S, Zhao, Y et al.. Identification of a set of genes showing regionally enriched expression in the mouse brain. BMC Neurosci. 2008;9 :66. doi: 10.1186/1471-2202-9-66. PubMed PMID:18625066 PubMed Central PMC2483290.
Kumar, RA, McGhee, KA, Leach, S, Bonaguro, R, Maclean, A, Aguirre-Hernandez, R et al.. Initial association of NR2E1 with bipolar disorder and identification of candidate mutations in bipolar disorder, schizophrenia, and aggression through resequencing. Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008;147B (6):880-9. doi: 10.1002/ajmg.b.30696. PubMed PMID:18205168 .
Kumar, RA, Everman, DB, Morgan, CT, Slavotinek, A, Schwartz, CE, Simpson, EM et al.. Absence of mutations in NR2E1 and SNX3 in five patients with MMEP (microcephaly, microphthalmia, ectrodactyly, and prognathism) and related phenotypes. BMC Med. Genet. 2007;8 :48. doi: 10.1186/1471-2350-8-48. PubMed PMID:17655765PubMed Central PMC1950490.
Oberlander, TF, Bonaguro, RJ, Misri, S, Papsdorf, M, Ross, CJ, Simpson, EM et al.. Infant serotonin transporter (SLC6A4) promoter genotype is associated with adverse neonatal outcomes after prenatal exposure to serotonin reuptake inhibitor medications. Mol. Psychiatry. 2008;13 (1):65-73. doi: 10.1038/sj.mp.4002007. PubMed PMID:17519929 .
Kumar, RA, Leach, S, Bonaguro, R, Chen, J, Yokom, DW, Abrahams, BS et al.. Mutation and evolutionary analyses identify NR2E1-candidate-regulatory mutations in humans with severe cortical malformations. Genes Brain Behav. 2007;6 (6):503-16. doi: 10.1111/j.1601-183X.2006.00277.x. PubMed PMID:17054721 PubMed Central PMC2040186.
Houde, C, Dickinson, RJ, Houtzager, VM, Cullum, R, Montpetit, R, Metzler, M et al.. Hippi is essential for node cilia assembly and Sonic hedgehog signaling. Dev. Biol. 2006;300 (2):523-33. doi: 10.1016/j.ydbio.2006.09.001. PubMed PMID:17027958 PubMed Central PMC5053816.
Devon, RS, Orban, PC, Gerrow, K, Barbieri, MA, Schwab, C, Cao, LP et al.. Als2-deficient mice exhibit disturbances in endosome trafficking associated with motor behavioral abnormalities. Proc. Natl. Acad. Sci. U.S.A. 2006;103 (25):9595-600. doi: 10.1073/pnas.0510197103. PubMed PMID:16769894 PubMed Central PMC1480452.
Kuo, BY, Chen, Y, Bohacec, S, Johansson, O, Wasserman, WW, Simpson, EM et al.. SAGE2Splice: unmapped SAGE tags reveal novel splice junctions. PLoS Comput. Biol. 2006;2 (4):e34. doi: 10.1371/journal.pcbi.0020034. PubMed PMID:16683015 PubMed Central PMC1447652.
Siddiqui, AS, Khattra, J, Delaney, AD, Zhao, Y, Astell, C, Asano, J et al.. A mouse atlas of gene expression: large-scale digital gene-expression profiles from precisely defined developing C57BL/6J mouse tissues and cells. Proc. Natl. Acad. Sci. U.S.A. 2005;102 (51):18485-90. doi: 10.1073/pnas.0509455102. PubMed PMID:16352711 PubMed Central PMC1311911.
Christie, BR, Li, AM, Redila, VA, Booth, H, Wong, BK, Eadie, BD et al.. Deletion of the nuclear receptor Nr2e1 impairs synaptic plasticity and dendritic structure in the mouse dentate gyrus. Neuroscience. 2006;137 (3):1031-7. doi: 10.1016/j.neuroscience.2005.08.091. PubMed PMID:16289828 .
Abrahams, BS, Kwok, MC, Trinh, E, Budaghzadeh, S, Hossain, SM, Simpson, EM et al.. Pathological aggression in "fierce" mice corrected by human nuclear receptor 2E1. J. Neurosci. 2005;25 (27):6263-70. doi: 10.1523/JNEUROSCI.4757-04.2005. PubMed PMID:16000615 .
Janssen, PA, Nicholls, TL, Kumar, RA, Stefanakis, H, Spidel, AL, Simpson, EM et al.. Of mice and men: will the intersection of social science and genetics create new approaches for intimate partner violence?. J Interpers Violence. 2005;20 (1):61-71. doi: 10.1177/0886260504268120. PubMed PMID:15618562 .
Houde, C, Banks, KG, Coulombe, N, Rasper, D, Grimm, E, Roy, S et al.. Caspase-7 expanded function and intrinsic expression level underlies strain-specific brain phenotype of caspase-3-null mice. J. Neurosci. 2004;24 (44):9977-84. doi: 10.1523/JNEUROSCI.3356-04.2004. PubMed PMID:15525783 .
Fedele, DE, Koch, P, Scheurer, L, Simpson, EM, Möhler, H, Brüstle, O et al.. Engineering embryonic stem cell derived glia for adenosine delivery. Neurosci. Lett. 2004;370 (2-3):160-5. doi: 10.1016/j.neulet.2004.08.031. PubMed PMID:15488315 .
Hossain, SM, Wong, BK, Simpson, EM. The dark phase improves genetic discrimination for some high throughput mouse behavioral phenotyping. Genes Brain Behav. 2004;3 (3):167-77. doi: 10.1111/j.1601-183x.2004.00069.x. PubMed PMID:15140012 .
Kumar, RA, Chan, KL, Wong, AH, Little, KQ, Rajcan-Separovic, E, Abrahams, BS et al.. Unexpected embryonic stem (ES) cell mutations represent a concern in gene targeting: lessons from "fierce" mice. Genesis. 2004;38 (2):51-7. doi: 10.1002/gene.20001. PubMed PMID:14994267 .
Banks, KG, Johnson, KA, Lerner, CP, Mahaffey, CL, Bronson, RT, Simpson, EM et al.. Retroposon compensatory mechanism hypothesis not supported: Zfa knockout mice are fertile. Genomics. 2003;82 (3):254-60. . PubMed PMID:12906850 .
Abrahams, BS, Chong, AC, Nisha, M, Milette, D, Brewster, DA, Berry, ML et al.. Metaphase FISHing of transgenic mice recommended: FISH and SKY define BAC-mediated balanced translocation. Genesis. 2003;36 (3):134-41. doi: 10.1002/gene.10205. PubMed PMID:12872244 .
Slow, EJ, van Raamsdonk, J, Rogers, D, Coleman, SH, Graham, RK, Deng, Y et al.. Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease. Hum. Mol. Genet. 2003;12 (13):1555-67. . PubMed PMID:12812983 .
Simpson, EM, Johnson, KA, Shirley, BJ, Fang, GY, Bayleran, JK, Lerner, CP et al.. Novel Sxr(a) ES cell line offers hope for Y chromosome gene-targeted mice. Genesis. 2002;33 (2):62-6. doi: 10.1002/gene.10093. PubMed PMID:12112873 .
Abrahams, BS, Mak, GM, Berry, ML, Palmquist, DL, Saionz, JR, Tay, A et al.. Novel vertebrate genes and putative regulatory elements identified at kidney disease and NR2E1/fierce loci. Genomics. 2002;80 (1):45-53. . PubMed PMID:12079282 .
Young, KA, Berry, ML, Mahaffey, CL, Saionz, JR, Hawes, NL, Chang, B et al.. Fierce: a new mouse deletion of Nr2e1; violent behaviour and ocular abnormalities are background-dependent. Behav. Brain Res. 2002;132 (2):145-58. . PubMed PMID:11997145 PubMed Central PMC2862907.
Collins, EC, Pannell, R, Simpson, EM, Forster, A, Rabbitts, TH. Inter-chromosomal recombination of Mll and Af9 genes mediated by cre-loxP in mouse development. EMBO Rep. 2000;1 (2):127-32. doi: 10.1038/sj.embor.embor616. PubMed PMID:11265751 PubMed Central PMC1084253.
Linnell, ER, Lerner, CP, Johnson, KA, Leach, CA, Ulrich, TR, Rafferty, WC et al.. Transgenic mice for the preparation of puromycin-resistant primary embryonic fibroblast feeder layers for embryonic stem cell selection. Mamm. Genome. 2001;12 (2):169-71. . PubMed PMID:11210188 .
Bergstrom, DE, Grieco, DA, Sonti, MM, Fawcett, JJ, Bell-Prince, C, Cram, LS et al.. The mouse Y chromosome: enrichment, sizing, and cloning by bivariate flow cytometry. Genomics. 1998;48 (3):304-13. doi: 10.1006/geno.1997.5176. PubMed PMID:9545635 .
George, JF, Sweeney, SD, Kirklin, JK, Simpson, EM, Goldstein, DR, Thomas, JM et al.. An essential role for Fas ligand in transplantation tolerance induced by donor bone marrow. Nat. Med. 1998;4 (3):333-5. . PubMed PMID:9500608 .
Anon. Mutant mice and neuroscience: recommendations concerning genetic background. Banbury Conference on genetic background in mice. Neuron. 1997;19 (4):755-9. . PubMed PMID:9354323 .
Bergstrom, DE, Yan, H, Sonti, MM, Narayanswami, S, Bayleran, JK, Simpson, EM et al.. An expanded collection of mouse Y chromosome RDA clones. Mamm. Genome. 1997;8 (7):510-2. . PubMed PMID:9195997 PubMed Central PMC2700750.
Mbikay, M, Tadros, H, Ishida, N, Lerner, CP, De Lamirande, E, Chen, A et al.. Impaired fertility in mice deficient for the testicular germ-cell protease PC4. Proc. Natl. Acad. Sci. U.S.A. 1997;94 (13):6842-6. . PubMed PMID:9192653PubMed Central PMC21246.
Aubrecht, J, Goad, ME, Simpson, EM, Schiestl, RH. Expression of hygR in transgenic mice causes resistance to toxic effects of hygromycin B in vivo. J. Pharmacol. Exp. Ther. 1997;281 (2):992-7. . PubMed PMID:9152410 .
Simpson, EM, Linder, CC, Sargent, EE, Davisson, MT, Mobraaten, LE, Sharp, JJ et al.. Genetic variation among 129 substrains and its importance for targeted mutagenesis in mice. Nat. Genet. 1997;16 (1):19-27. doi: 10.1038/ng0597-19. PubMed PMID:9140391 .
Enerbäck, S, Jacobsson, A, Simpson, EM, Guerra, C, Yamashita, H, Harper, ME et al.. Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature. 1997;387 (6628):90-4. doi: 10.1038/387090a0. PubMed PMID:9139827 .
Mahaffey, CL, Bayleran, JK, Yeh, GY, Lee, TC, Page, DC, Simpson, EM et al.. Intron/exon structure confirms that mouse Zfy1 and Zfy2 are members of the ZFY gene family. Genomics. 1997;41 (1):123-7. doi: 10.1006/geno.1997.4611. PubMed PMID:9126493 .
Borriello, F, Sethna, MP, Boyd, SD, Schweitzer, AN, Tivol, EA, Jacoby, D et al.. B7-1 and B7-2 have overlapping, critical roles in immunoglobulin class switching and germinal center formation. Immunity. 1997;6 (3):303-13. . PubMed PMID:9075931 .
Navin, A, Prekeris, R, Lisitsyn, NA, Sonti, MM, Grieco, DA, Narayanswami, S et al.. Mouse Y-specific repeats isolated by whole chromosome representational difference analysis. Genomics. 1996;36 (2):349-53. doi: 10.1006/geno.1996.0473. PubMed PMID:8812464 .
Bayleran, JK, Yan, H, Hopper, CA, Simpson, EM. Frequencies of cystic fibrosis mutations in the Maine population: high proportion of unknown alleles in individuals of French-Canadian ancestry. Hum. Genet. 1996;98 (2):207-9. . PubMed PMID:8698344 .
Mbikay, M, Tadros, H, Seidah, NG, Simpson, EM. Linkage mapping of the gene for the LIM-homeoprotein LIM3 (locus Lhx3) to mouse chromosome 2. Mamm. Genome. 1995;6 (11):818-9. . PubMed PMID:8597642 .
Johnson, KA, Lerner, CP, Di Lacio, LC, Laird, PW, Sharpe, AH, Simpson, EM et al.. Transgenic mice for the preparation of hygromycin-resistant primary embryonic fibroblast feeder layers for embryonic stem cell selections. Nucleic Acids Res. 1995;23 (7):1273-5. . PubMed PMID:7739908 PubMed Central PMC306843.
Mbikay, M, Seidah, NG, Chrétien, M, Simpson, EM. Chromosomal assignment of the genes for proprotein convertases PC4, PC5, and PACE 4 in mouse and human. Genomics. 1995;26 (1):123-9. . PubMed PMID:7782070 .
Zambrowicz, BP, Findley, SD, Simpson, EM, Page, DC, Palmiter, RD. Characterization of the murine Zfy1 and Zfy2 promoters. Genomics. 1994;24 (2):406-8. . PubMed PMID:7698773 .
Zambrowicz, BP, Zimmermann, JW, Harendza, CJ, Simpson, EM, Page, DC, Brinster, RL et al.. Expression of a mouse Zfy-1/lacZ transgene in the somatic cells of the embryonic gonad and germ cells of the adult testis. Development. 1994;120 (6):1549-59. . PubMed PMID:8050362 .
Simpson, EM, Page, DC. An interstitial deletion in mouse Y chromosomal DNA created a transcribed Zfy fusion gene. Genomics. 1991;11 (3):601-8. . PubMed PMID:1774064 .
Page, DC, Disteche, CM, Simpson, EM, de la Chapelle, A, Andersson, M, Alitalo, T et al.. Chromosomal localization of ZFX--a human gene that escapes X inactivation--and its murine homologs. Genomics. 1990;7 (1):37-46. . PubMed PMID:1970799 .
Mardon, G, Luoh, SW, Simpson, EM, Gill, G, Brown, LG, Page, DC et al.. Mouse Zfx protein is similar to Zfy-2: each contains an acidic activating domain and 13 zinc fingers. Mol. Cell. Biol. 1990;10 (2):681-8. . PubMed PMID:2105457 PubMed Central PMC360866.
Page, DC, Mosher, R, Simpson, EM, Fisher, EM, Mardon, G, Pollack, J et al.. The sex-determining region of the human Y chromosome encodes a finger protein. Cell. 1987;51 (6):1091-104. . PubMed PMID:3690661 .
Himmelfarb, HJ, Simpson, EM, Friesen, JD. Isolation and characterization of temperature-sensitive RNA polymerase II mutants of Saccharomyces cerevisiae. Mol. Cell. Biol. 1987;7 (6):2155-64. . PubMed PMID:3299061PubMed Central PMC365338.
Elliott, EM, Henderson, G, Sarangi, F, Ling, V. Complete sequence of three alpha-tubulin cDNAs in Chinese hamster ovary cells: each encodes a distinct alpha-tubulin isoprotein. Mol. Cell. Biol. 1986;6 (3):906-13. . PubMed PMID:3773896 PubMed Central PMC367591.
Elliott, EM, Sarangi, F, Henderson, G, Ling, V. Cloning of 11 alpha-tubulin gene sequences from the genome of Chinese hamster ovary cells. Can. J. Biochem. Cell Biol. 1985;63 (6):511-8. doi: 10.1139/o85-070. PubMed PMID:2931165 .
Elliott, EM, Okayama, H, Sarangi, F, Henderson, G, Ling, V. Differential expression of three alpha-tubulin genes in Chinese hamster ovary cells. Mol. Cell. Biol. 1985;5 (1):236-41. . PubMed PMID:3982416 PubMed Central PMC366698.
Elliott, EM, Ling, V. Selection and characterization of Chinese hamster ovary cell mutants resistant to melphalan (L-phenylalanine mustard). Cancer Res. 1981;41 (2):393-400. . PubMed PMID:7448783 .
