Joseph Gleeson, M.D.
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Professor of Neuroscience and Pediatrics
UC San Diego School of Medicine
Investigator
Howard Hughes Medical Institute
Research ProfileDr. Gleeson is the head of the Neurogenetics Laboratory at UCSD and the Director of the Center for Brain Development, the goal of which is to understand the genetic basis of pediatric brain diseases. He is the author of the authoritative chapters on brain diseases in major medical textbooks. He is also the Director of the UCSD Microscopy Core and leads many initiatives in the area of neuroscience, genetics and cell biology at UCSD.
Dr. Gleeson is committed to developing improved diagnostics and treatments for children with neurodevelopmental conditions. He has a focus on structural brain diseases of the cortex, cerebellum and brainstem. The lab is interested in identifying the whole spectrum of various genetic causes, and then working collaboratively to understand basic mechanisms of disease. This information should lead to new treatments for disease.
Ulrich Mueller, Ph.D.
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Director
Dorris Neuroscience Center
Professor
The Scripps Research Institute
Research ProfileDr. Mueller's laboratory has extensive experience in mouse molecular genetics and the analysis of developmental defects that affect multiple organ systems including the central nervous system, inner ear, muscle and kidney. His lab has generated dozens of mice with genetic modifications using transgenic, knock-in and knock-out approaches; this includes mice for conventional and conditional (CRE/LOX, tTA) mutagenesis.
The lab also had experience in handling large-scale mouse projects. They have carried out a broad ENU mutagenesis screen to identify mouse lines with recessive deafness traits, which used more than 30,000 mice for phenotyping and positional cloning. Dr. Mueller is one of the principal investigators heading one of three NIH Neuroscience Blueprint Centers in the US that generates hundreds of CRE mouse lines for the neuroscience community.
He also serves as faculty advisor of the Scripps Mouse Genetics Core and supervises the generation and cryopreservation of mouse lines for all research laboratories at Scripps. Therefore, his laboratory has all the necessary expertise to generate, characterize and maintain the mouse lines necessary for this current project.
Neil Chi, M.D., Ph.D.
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Assistant Professor
Department of Medicine
UC San Diego School of Medicine
Research Profile
Lab WebsiteOur goal is to investigate the central mechanisms of structural brain defects (SBD). Specifically, we will perform in vivo cellular, molecular, and genetic analysis on zebrafish SBD mutants and morphants in order to analyze the fundamental mechanisms that guide vertebrate brain morphogenesis and function during central nervous system (CNS) development. These studies will employ techniques that our laboratory routinely uses to study the developmental programs for organogenesis and include immunohistochemical confocal microscopy imaging, in vivo cell morphometric analysis, time-lapse in vivo brain imaging using neurai specific transgenic lines, and transgene-assisted forward genetic screens.
The zebrafish is typically used as an outstanding fonward genetic vertebrate system for studying developmental embryologic events. However, because of my medical training, I realized that the system was limited in its ability to analyze and model the pathophysiology of human diseases. Thus, I created a new calcium sensitive GFP (gCaMP) transgenic line to develop a novel in vivo calcium imaging system for analyzing the electrical activity of the zebrafish heart. Using this tool, we have performed fon/vard genetic screens to identify and analyze novel zebrafish cardiac conduction mutants to dissect cellular and molecular pathways that regulate the development of the vertebrate cardiac conduction system (Chi et al., 2008 PLoS biology).
Furthermore, exploiting the optical transparency of zebrafish, our group has generated a collection of zebrafish transgenics to investigate in vivo the morphogenetic events that transpire during cardiac development (Chi et al., 2008 Genes and Development, Chi et al., 2010 PNAS).
Finally, in collaboration with Henwig Baler at UCSF, we have performed a Tol2 enhancer trap Gal4 driver screen to generate a library of new brain specific Gal4 driver lines that permit detailed analysis of CNS/brain development as well as neural activity during behavioral responses (Scott et al., 2006 Nature Methods). Overall, these techniques and tools will be particularly useful towards our proposed fonward genetic screens of SBD mutants as well as the cellular, molecular, and genetic analysis of brain morphogenesis and function.
Thus, our lab's expertise in using the zebrafish to study the underlying mechanisms of vertebrate organogenesis synergizes well with our colleagues using mammalian systems including mouse and human to study brain morphogenesis. Toward this end, the Gleeson lab already collaborates with our lab to study the role of polarity genes and primary cilia in cardiovascular and neural development/function. Furthermore, we currently collaborate with the Frazer lab to perform Next Generation sequencing and genomic analysis of human pluripotent stem cell derived cardiac lineages.
Because of the proximity of our labs, this sharing of reagents, ideas and expertise has been straightforward and seamless. Thus, we anticipate that these past collaborations with the Co-Pls of this proposal will facilitate the execution of our proposed studies to elucidate the underlying mechanisms involved in brain structure and function.
Overall, we believe the full potential of this proposal will be to ultimately provide novel insights into the mechanisms of how polarity genes may influence brain morphogenesis and function, and my past successful and productive research on using the zebrafish to understand the developmental programs of organogenesis has provided me the background and expertise to co-lead the proposed project.
Kelly Frazer, Ph.D.
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Chief
Division of Genome Information Sciences
Professor
Department of Pediatrics
UC San Diego School of Medicine
Lab WebsiteDr. Frazer joined the faculty at UC San Diego in 2009 as a Professor in the Department of Pediatrics and the founding Chief of the Division of Genome Information Sciences. The goal of her research is to understand genetic predisposition to complex diseases including cancer starting in childhood but spanning the whole age spectrum.
Dr. Frazer’s laboratory is located in the UCSD Moores Cancer Center, where she is the Program Leader of the Cancer Genes and Genome Program and is actively working with physician-scientists on a variety of projects to analyze somatic mutations underlying tumorigenesis and to identify new therapeutic targets. Dr. Frazer is a member of UC San Diego’s Institute for Genomic Science and the Director of the Bio-Computational Center (BCC) at the university’s Altman Clinical and Translational Research Institute (ACTRI).
In her role as director of the BCC Dr. Frazer shares her expertise with numerous UC San Diego investigators to ensure they have access to state of the art genomic methods and effective data analysis.
Vineet Bafna, Ph.D.
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Professor
Computer Science Department
Institute for Genomic Medicine
UC San Diego
Research WebsiteDr. Bafna's role in this project is to lead the Bioinformatics Core. Specifically, he will develop and support the pipeline for analysis of Next Generation Sequencing (NGS), and exome sequencing data for the detection of variants associated with specific phenotypes.
Part of this will require the development of large data storage, organization and retrieval methods for NGS, and part will require the development of new algorithms for data analysis, variant prioritization, interrogation of newly emerged datasets, and methodology for validation of putative mutations within a functional mechanistic framework.