Grant: Foundation Grant

Brain Disease; Cellular Models; Genetics; High Throughput Sequencing (Exomes And Whole Genomes); Molecular Biology; Mouse Models; Neurodegeneration; Neurological Disorders; Pathological Mechanisms; Protein Biology

<html> <body> <p> <b><i><u>Overarching Direction</u></i>:</b> Brain diseases are a great burden to many people and society. This project will allow me to identify the genetic causes and improve our understanding of the pathogenesis of three important diseases: amyotrophic lateral sclerosis (ALS), schizophrenia (SCZ) and essential tremor (ET). For gene identification, I will use NextGen sequencing (NGS) and the most advanced bioinformatics methods to explore new ground, such as the identification of oligogenic intermediate penetrance genetic factors and the role of somatic mutations in ALS. I will use my broad experience in biological validation to study the consequences of mutations, focusing on how to best translate these discoveries into medical practice. To remain at the cutting edge and generate new knowledge I will continue to rapidly adopt the newest relevant technologies (eg. iPSC, CRISPR). For ALS I will also build a drug discovery platform using ALS relevant cells derived from induced pluripotent stem cells (iPSC) prepared from patients.</p> <p> <br> <b><i><u>Results &amp; Advances</u></i></b><b><i>:</i></b> The three diseases are distinct but all have large unidentified genetic components, are complex, are difficult to accurately diagnose and are poorly treated. Identification of many additional disease predisposing genes will allow the definition of the pathways relevant to each disease as well as the creation of disease relevant models (iPSC, animal models, etc) that can be used to understand pathogenesis and evaluate new treatments. For ALS, establishing a causative role for somatic mutations in the spinal cord could explain the cause of a significant fraction of sporadic ALS cases. The ALS drug screen will identify therapeutically relevant pioneer targets. Early intervention leads to a noticeably better outcome SCZ. Identifying an important fraction of SCZ predisposing genes could allow a molecular redefinition of SCZ and the development of a diagnostic tool for early diagnosis. Finding ET causative genes will allow molecular diagnostics and the development of relevant models for screening for treatments.</p> <p> <br> <b><i><u>Nature of expertise</u></i></b><b>:</b> I am a Neurologist and Geneticist with a strong track record in neurogenetics. I have identified several genes causing/predisposing to Mendelian and complex disorders; and have significantly contributed to understanding pathogenesis of many diseases. I built a large academic NGS bioinformatics unit and have a staff experienced in genetics and biology. My ongoing collaborations and involvement in large collaborative efforts in ALS, SCZ and ET will ensure continued access to critically important biosamples. My studies also require expert collaborators in statistics, which I have. For biological studies my lab is experienced with conventional mammalian models; for work in other systems (eg. zebrafish, <i>C. elegans</i> and iPSC/neuron cells) I have an established network of excellent collaborators.</p> <p> <br> <b><i><u>Mentoring &amp; training</u></i></b><b>:</b> McGill&rsquo;s departments of Human Genetics and Neurology &amp; Neurosurgery provide me with access to excellent students/fellows. The Montreal Neurological Institute offers an excellent environment to train personnel. I promote a <i>&ldquo;hands-on&rdquo;</i> approach so that trainees develop a deep understanding of what they are doing and of the difficulties inherent to experimental science. Special working groups are formed within the lab, and with other labs, to develop methods, contribute to challenging projects or advance collaborations. Over the years my students have done tremendously well.</p> </body> </html>