Research Projects

The overall goal of my research program is to use genetically engineered mouse models to understand and improve treatment for human brain and behaviour disorders. My approach is to study the genetics, behaviour, neurogenesis, and genome-wide transcription in mouse models of brain disorders. The expectation is that a clearer understanding of abnormal behaviour and brain pathologies in humans will lead to new and improved therapeutic strategies for these devastating conditions.

Scientists are only beginning to tap the power of wedding 'genetic engineering' with 'brain and behaviour studies to address critical problems in our society. In the Simpson laboratory, we are helping to lead the way in this important new field.

BIPOLAR DISORDER AND NR2E1

While conducting research at The Jackson Laboratory (Maine, USA), my group discovered a novel mouse mutation named 'fierce'. These mice lack the Nr2e1 (Nuclear Receptor 2E1) gene and display extreme violent behaviour; with males often injuring or killing siblings or intended mates. Females also show increased aggression and 50% of dams abandon their pups shortly after birth. Both sexes have brain and eye abnormalities including differential hypoplasia of the forebrain and retina.

Recently, we demonstrated that the pathological aggression in ‘fierce’ mice can be corrected by the human NR2E1 gene. ‘Fierce’ mice lacking the mouse Nr2e1 gene, but carrying a copy of the human gene, showed normal brain development and behaviour. This work demonstrates the functional equivalency of the human and mouse genes when tested in mouse, and establishes a system to functionally evaluate the role of human genes in psychiatric disease.

NR2E1 resides within a chromosomal locus for bipolar disorder and schizophrenia. In addition, Nr2e1-null mice show altered neurogenesis, cortical and limbic abnormalities, aggression, hyperexcitability, and cognitive impairment. Thus, NR2E1 is a positional and functional candidate for involvement in mental illness. We performed genetic association analyses in 394 patients with bipolar disorder, 396 with schizophrenia, and 479 controls using six common markers and haplotypes. We also performed a mutation screen of NR2E1 by resequencing 126 humans with bipolar disorder, schizophrenia, or aggressive disorders. NR2E1 was associated with bipolar disorder I and II with an odds ratio of 0.77 (P=0.013), which remained significant after correcting for multiple comparisons. We identified eight novel candidate mutations that were absent in 325 controls. This data supports the hypothesis that genetic variation at human NR2E1 may be involved in susceptibility to brain-behaviour disorders.

PLEIADES PROMOTER PROJECT: GENOME RESOURCES ADVANCING THERAPIES FOR BRAIN DISORDERS

I lead the Pleiades Promoter Project, a $10.2 million, four year, Genome Canada research initiative building neurogenomic tools to advance research and gene-driven therapies for brain and eye disorders. Towards this end, we have used a myriad of bioinformatic and expression data, including 67 SAGE libraries from mouse brain development that we produced as part of a previous Genome Canada and Genome BC project (Mouse Atlas of Gene Expression Project). From this starting point, Pleiades has designed and is building 250 human DNA promoters of 4 kb or less to drive gene expression in brain and eye regions of therapeutic interest. 205 of these promoters are being tested in knock-in mice, which are being examined by histochemistry to visualize the expression domain of the reporters (EGFP, EGFPcre or lacZ). Target regions include those important in Alzheimer, Parkinson, Huntington, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, Spinocerebellar Ataxia, Depression, ADHD, Autism, Cancer, and Aniridia.

This research endeavor involves seven principal investigators (PIs) with laboratories in both Canada and the USA. Each of the seven PIs are experts in their fields, including chromatin structure, genomic regulation, large scale molecular biology, ESCs and knock-in mice, and neurophenotyping. To ensure the wide distribution of these resources, the team has collaborated with International BioPharma Solutions Ltd.. Pleiades is also working with the UBC School of Journalism to explore the challenging interface between science and journalism with a focus on genomics and gene therapy (http://www.sciencejournalism.net/).

ANIRIDIA AND NR2E1

Aniridia is a rare congenital eye disorder characterized by underdevelopment of the iris. However, it usually involves the entirety of both eyes and results in blindness. It can be inherited or occur spontaneously, and in 80% of cases mutations in PAX6 cause the disorder. However, in ~20% of patients with Aniridia and related disorders, no causative mutation has been identified and so there is no explanation of these patients’ disorder, nor is gene-based counseling available to them.

Work in the Simpson laboratory, amongst others, has shown that NR2E1 (Nuclear Receptor 2E1) is a gene so like PAX6 that it has become a candidate to explain Aniridia in the remaining ~20% of patients. Both genes are transcription factors expressed in stem cells of the brain and eye, where they are critical for maintaining the correct balance between proliferation and differentiation. The two genes interact genetically, and too much or too little of either is detrimental to eye development in the mouse. Finally, both Nr2e1 and Pax6 mutant mice display eye abnormalities including microphthalmia, anophthalmia, hypoplasia of the optic nerve (present in ~75% of patients), ectopic lentis (also in 18-35% of patients), and corneal opacity (present in most patients).

To test the hypothesis that mutations in NR2E1 can cause Aniridia, the Simpson Laboratory is crossing Pax6 underexpressing mutant mice with Nr2e1 overexpressing mice in anticipation of the alleles complementing each other and preventing mouse Aniridia. In addition, we have started sequencing DNA samples from patients diagnosed with Aniridia who do not have mutations in their PAX6 gene. From this work we expect to identify novel candidate mutations in the NR2E1 gene that can explain the origin of eye disorder in the remaining 20% of patients with Aniridia.