Grant: Foundation Grant

University of British Columbia

$2,647,918.00

Molecular analysis of synapse development

EF 2014-15

Résumé

<span data-mce-style="font-size: 11.0pt;" style="font-size:11.0pt;font-family:"Calibri","sans-serif"; mso-ascii-theme-font:minor-latin;mso-fareast-font-family:Calibri;mso-fareast-theme-font: minor-latin;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;mso-ansi-language:EN-US;mso-fareast-language: EN-US;mso-bidi-language:AR-SA">Our overall goal is to understand molecular mechanisms underlying the development and plasticity of synapses, the basic units of communication in the brain, and apply this knowledge towards treating neuropsychiatric disorders. We assembled an expert team of trainees and international collaborators and propose a unique program characterizing triggers for excitatory and inhibitory synapse development and regulators of neurotransmitter receptors. Genetic evidence implicates alterations in synapses and imbalances in excitatory/inhibitory neurotransmission as major contributors to autism and schizophrenia. Our research program places disease-linked genes into functional pathways for interpreting and translating genetic data, and will develop and test new targeted therapeutic approaches. One focus of our research is inhibitory postsynaptic signaling components, key clinical targets but under-studied compared with excitatory synapses. We used a combined transgenic-proteomics approach to identify new inhibitory synaptic proteins. A second focus is cell surface synapse organizing proteins that trigger the local recruitment of neurotransmitter release and reception machinery. We showed that neurexins and neuroligins function bidirectionally to trigger excitatory and inhibitory synapse development. From an unbiased screen, we found new factors including LRRTMs and Clstn3 and characterized their <span data-mce-style="font-size: 11.0pt;" style="font-size:11.0pt;font-family:"Calibri","sans-serif"; mso-ascii-theme-font:minor-latin;mso-fareast-font-family:Calibri;mso-fareast-theme-font: minor-latin;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;mso-ansi-language:EN-US;mso-fareast-language: EN-US;mso-bidi-language:AR-SA">selectivity for excitatory or inhibitory synapses and <span data-mce-style="font-size: 11.0pt;" style="font-size:11.0pt;font-family:"Calibri","sans-serif"; mso-ascii-theme-font:minor-latin;mso-fareast-font-family:Calibri;mso-fareast-theme-font: minor-latin;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;mso-ansi-language:EN-US;mso-fareast-language: EN-US;mso-bidi-language:AR-SA">binding to presynaptic neurexins. Mutations in neurexins, neuroligins and LRRTMs increase risk of neuropsychiatric disorders; e.g. NRXN1 is the gene most strongly linked to non-syndromic autism. In the proposed research, we designed new approaches to complete identification of the full set of synapse organizing proteins. To understand the physiological and pathological roles of these genes, we will characterize mouse models with targeted mutations. We are also identifying regulators and downstream effectors. We identified MDGAs, also strongly linked to autism and schizophrenia, as negative regulators that bind neuroligins and prevent them from binding neurexins, thus suppressing synapse development. In the next phase of research, we will test peptides targeting such interactions for their ability to up- or down-regulate excitatory and inhibitory synapse function and to ameliorate deficits in animal models. This research will significantly advance knowledge of the causes and pathophysiology of neuropsychiatric disorders as well as of normal brain development. It is my belief that this fundamental research based on human genetics is the best way to combat autism and schizophrenia, to <span data-mce-style="font-size: 11.0pt;" style="font-size:11.0pt;font-family:"Calibri","sans-serif"; mso-ascii-theme-font:minor-latin;mso-fareast-font-family:Calibri;mso-fareast-theme-font: minor-latin;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;mso-ansi-language:EN-US;mso-fareast-language: EN-US;mso-bidi-language:AR-SA">first identify targets, and second develop effective therapeutics. <span data-mce-style="font-size: 11.0pt;" style="font-size:11.0pt;font-family:"Calibri","sans-serif"; mso-ascii-theme-font:minor-latin;mso-fareast-font-family:Calibri;mso-fareast-theme-font: minor-latin;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;mso-ansi-language:EN-US;mso-fareast-language: EN-US;mso-bidi-language:AR-SA">The knowledge will be conveyed to key users, through an international effort for interpreting large scale genetic studies, and to companies for developing drugs targeting autism. A second important output will be in the form of trainees rigorously prepared for research with additional specialization for teaching or industry careers. Finally, we will put more of our efforts into translation and hope that our peptide approach will result directly in effective therapeutics for neuropsychiatric disorders. Although our main focus is neurodevelopmental disorders based on the genetic underpinnings, such reagents selectively targeting excitatory or inhibitory synapses are likely to be more broadly useful for other disorders such as epilepsy and neurodegeneration.

Ministère

Canadian Institutes of Health Research

Programme

Foundation Grant

Bénéficiaire

University of British Columbia

Emplacement

British Columbia, Canada

Type de bénéficiaire

Academia

Type

Grant

Source

CIHR Funding Decisions Database

Tel que publié

312557

Name

Craig Ann Marie

Region

British Columbia

Country

Canada

Orgtype

Institution Paid; Research Institution

Instname2

Neurosciences, Mental Health and Addiction

Theme2

Biomedical

Prcname2

Foundation Grant

Projecttitle

Molecular analysis of synapse development

Programtype2

Operating Grants

Orgnameinp2

University of British Columbia

Cihramount2

$2,647,918

Cihrequipment2

Programname2

Foundation Grant

Keyworddelim

Animal Model; Autism Spectrum Disorders; Brain Development; Cell Adhesion Molecule; Cell Biology; Cell Culture; Molecular Genetics; Molecular Neurobiology; Neurotransmitter Receptor; Synaptogenesis

Competitiondate

201409

Approvedterm2

7 yrs 0 mth

Pinamesdelim

Craig, Ann Marie

Approvedterm

7 ans 0 mois

Cihrcontribution2

~ $2,647,918~ $0~

Abstract

<html> <body> <span data-mce-style="font-size: 11.0pt;" style="font-size:11.0pt;font-family:"Calibri","sans-serif"; mso-ascii-theme-font:minor-latin;mso-fareast-font-family:Calibri;mso-fareast-theme-font: minor-latin;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;mso-ansi-language:EN-US;mso-fareast-language: EN-US;mso-bidi-language:AR-SA">Our overall goal is to understand molecular mechanisms underlying the development and plasticity of synapses, the basic units of communication in the brain, and apply this knowledge towards treating neuropsychiatric disorders. We assembled an expert team of trainees and international collaborators and propose a unique program characterizing triggers for excitatory and inhibitory synapse development and regulators of neurotransmitter receptors. Genetic evidence implicates alterations in synapses and imbalances in excitatory/inhibitory neurotransmission as major contributors to autism and schizophrenia. Our research program places disease-linked genes into functional pathways for interpreting and translating genetic data, and will develop and test new targeted therapeutic approaches.<br> <br> One focus of our research is inhibitory postsynaptic signaling components, key clinical targets but under-studied compared with excitatory synapses. We used a combined transgenic-proteomics approach to identify new inhibitory synaptic proteins. A second focus is cell surface synapse organizing proteins that trigger the local recruitment of neurotransmitter release and reception machinery. We showed that neurexins and neuroligins function bidirectionally to trigger excitatory and inhibitory synapse development. From an unbiased screen, we found new factors including LRRTMs and Clstn3 and characterized their</span> <span data-mce-style="font-size: 11.0pt;" style="font-size:11.0pt;font-family:"Calibri","sans-serif"; mso-ascii-theme-font:minor-latin;mso-fareast-font-family:Calibri;mso-fareast-theme-font: minor-latin;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;mso-ansi-language:EN-US;mso-fareast-language: EN-US;mso-bidi-language:AR-SA">selectivity for excitatory or inhibitory synapses and</span> <span data-mce-style="font-size: 11.0pt;" style="font-size:11.0pt;font-family:"Calibri","sans-serif"; mso-ascii-theme-font:minor-latin;mso-fareast-font-family:Calibri;mso-fareast-theme-font: minor-latin;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;mso-ansi-language:EN-US;mso-fareast-language: EN-US;mso-bidi-language:AR-SA">binding to presynaptic neurexins. Mutations in neurexins, neuroligins and LRRTMs increase risk of neuropsychiatric disorders; e.g. NRXN1 is the gene most strongly linked to non-syndromic autism.<br> <br> In the proposed research, we designed new approaches to complete identification of the full set of synapse organizing proteins. To understand the physiological and pathological roles of these genes, we will characterize mouse models with targeted mutations. We are also identifying regulators and downstream effectors. We identified MDGAs, also strongly linked to autism and schizophrenia, as negative regulators that bind neuroligins and prevent them from binding neurexins, thus suppressing synapse development. In the next phase of research, we will test peptides targeting such interactions for their ability to up- or down-regulate excitatory and inhibitory synapse function and to ameliorate deficits in animal models.<br> <br> This research will significantly advance knowledge of the causes and pathophysiology of neuropsychiatric disorders as well as of normal brain development. It is my belief that this fundamental research based on human genetics is the best way to combat autism and schizophrenia, to</span> <span data-mce-style="font-size: 11.0pt;" style="font-size:11.0pt;font-family:"Calibri","sans-serif"; mso-ascii-theme-font:minor-latin;mso-fareast-font-family:Calibri;mso-fareast-theme-font: minor-latin;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;mso-ansi-language:EN-US;mso-fareast-language: EN-US;mso-bidi-language:AR-SA">first identify targets, and second develop effective therapeutics.</span> <span data-mce-style="font-size: 11.0pt;" style="font-size:11.0pt;font-family:"Calibri","sans-serif"; mso-ascii-theme-font:minor-latin;mso-fareast-font-family:Calibri;mso-fareast-theme-font: minor-latin;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;mso-ansi-language:EN-US;mso-fareast-language: EN-US;mso-bidi-language:AR-SA">The knowledge will be conveyed to key users, through an international effort for interpreting large scale genetic studies, and to companies for developing drugs targeting autism. A second important output will be in the form of trainees rigorously prepared for research with additional specialization for teaching or industry careers. Finally, we will put more of our efforts into translation and hope that our peptide approach will result directly in effective therapeutics for neuropsychiatric disorders. Although our main focus is neurodevelopmental disorders based on the genetic underpinnings, such reagents selectively targeting excitatory or inhibitory synapses are likely to be more broadly useful for other disorders such as epilepsy and neurodegeneration.</span>    </body> </html>

Voir les données sources CIHR Funding Decisions Database (Canadian Institutes of Health Research)