Andrew Tomlinson
Columbia University Health Sciences
Project start date: 1998-01-01
Project end date: 2013-01-31
Sponsored Links Excellgen http://Excellgen.com
SIGNALING SPECIFICITY IN DROSOPHILA SERPENTINE RECEPTORS
Andrew Tomlinson, Assistant Professor
Genetics And Developmentcolumbia University Health Sciences
columbia University Medical Center
new York, Ny 100323702
Grant 5R01GM057043-04 from National Institute Of General Medical Sciences IRG: CBY
Abstract: hopes to increase understanding of the Hh and Wg signaling pathways by elucidating mechanisms about how the known components work and will identify new components in these pathways. Aim 1 will test the proposed model for Hh signaling, will map the domain of Smoothened that confers sensitivity to Ptc, and will test specificity of activating downstream components. Aim 2 will test the specific hypothesis that the serpentine receptors activate heterotrimeric G proteins. Aim 3 will use an elegant genetic screen to identify new genes in the Wg signaling pathway
Keywords: biological signal transduction, gene expression, receptor expression, receptor sensitivity G protein, genetic mapping Drosophilidae, chimeric protein
Project start date: 1998-01-01
Project end date: 2002-12-31
5R01GM057043-04 (2001): $269080
5R01GM057043-03 (2000): $261317
5R01GM057043-02 (1999): $253779
SIGNALING SPECIFICITY OF DROSOPHILA SERPENTINE RECEPTORS
Andrew Tomlinson, Principal Investigator
Columbia University Health Sciences, Columbia University Medical Center, New York, Ny 10032-3702
Grant 5R01GM057043-11 from National Institute Of General Medical Sciences
Abstract: Cellular polarization underlies many critical biological phenomena in wound healing, cells migrate to the site of lesion; neurons project axons that navigate to distant targets; and in the immune response, cells move to engulf invading pathogens. All these behaviors are mediated by the polarization of the cytoskeleton in response to external cues. A closely related phenomenon is called planar cell polarity (PCP). Here, cells arrayed in epithelia coordinately polarize so that all cells project their cuticular secretions in the same direction. Bird feathers, mammalian hairs and fish scales exemplify this phenomenon. This application is directed to understand how PCP is established. Drosophila is a model experimental organism in which PCP can be effectively investigated. Each cell uses a serpentine receptor called Frizzled (Fz) to decode an external gradient to direct its polarization. Serpentine receptors are typically transduced by trimeric G proteins, and the focus of this application is to understand the roles played by the fly G1o (and other PCP proteins) in Fz transduction and the organization of the cytoskeleton. We will use genetic, molecular and biochemical techniques to determine the exact relationship between Frizzled and G1o, and identify the proteins downstream of G1o in the transduction pathway. These studies will elucidate the mechanisms by which cells decode gradients, polarize their cytoskeletons, and communicate their actions to neighbors. Polarization of the cytoskeleton within cells is required for many critical bodily processes such as wound healing, formation of nerve connections, and the eradication of infection. A field of cells can coordinately organize their polarizations, as demonstrated by the organization of the cilliary bundles of the inner ear that permit us to hear sound. This application is designed to study planar cell polarity in fruit flies, to understand how cells can polarize and coordinate those polarizations in larger scale structures
Keywords: Aves; Avian; Axon; Behavior; Binding; Binding (Molecular Function); Biochemical; Biologic Phenomena; Biological Phenomena; Birds; Cell Communication and Signaling; Cell Polarity; Cell Signaling; Cells; Cellular Matrix; Chemotaxis; Complex; Cues; Cytoskeletal System; Cytoskeleton; Distant; Drosophila; Drosophila genus; Ear, Internal; Epithelium; Experimental Organism; Feathers; Fishes; Flies; Fruit Fly, Drosophila; G-Proteins; GDP Dissociation Factor; GDP Dissociation Stimulators; GDP Exchange Factors; GDP-GTP Exchange Protein; GDP-GTP Reversing Factors; GEF; GTP GDP exchange factor; GTP-Binding Proteins; GTP-Regulatory Proteins; Genes; Genetic; Genetic Techniques; Guanine Nucleotide Coupling Protein; Guanine Nucleotide Exchange Factors; Guanine Nucleotide Exchange Protein; Guanine Nucleotide Regulatory Proteins; Guanine Nucleotide Releasing Factors; Guanyl-Nucleotide Exchange Factor; Guanyl-Nucleotide Releasing Factor; Hair; Hearing; Immune response; Infection; Intracellular Communication and Signaling; Invaded; Laboratory Organism; Labyrinth; Lesion; Mediating; Methods and Techniques; Methods, Other; Modeling; Molecular; Molecular Genetic; Molecular Genetics; Molecular Interaction; Nerve; Nerve Cells; Nerve Unit; Nervous; Neural Cell; Neurocyte; Neurons; Pathway interactions; Phenotype; Play; Process; Proteins; Receptor Protein; Role; Signal Pathway; Signal Transduction; Signal Transduction Systems; Signaling; Site; Sound; Sound - physical agent; Specificity; Structure; Technics, Genetic; Techniques; Testing; Transducers; Wound Healing; Wound Repair; base; biological signal transduction; cellular polarity; design; designing; exchange factor; fly; fruit fly; gene function; gene product; hearing perception; host response; immunoresponse; inner ear; intracellular skeleton; neuronal; pathogen; pathway; polarized cell; protein complex; public health relevance; receptor; response; social role; sound; sound perception; tissue repair; tool
Relevance: Polarization of the cytoskeleton within cells is required for many critical bodily processes such as wound healing, formation of nerve connections, and the eradication of infection. A field of cells can coordinately organize their polarizations, as demonstrated by the organization of the cilliary bundles of the inner ear that permit us to hear sound. This application is designed to study planar cell polarity in fruit flies, to understand how cells can polarize and coordinate those polarizations in larger scale structures
Project start date: 1998-01-01
Project end date: 2013-01-31
Budget start date: 1-FEB-2010
Budget end date: 31-JAN-2011
PFA/PA: PA-07-070
5R01GM057043-11 (2010): $322438
5R01GM057043-09 (2007): $290048
5R01GM057043-08 (2006): $298711
5R01GM057043-07 (2005): $305900
Grants awarded to Andrew Tomlinson
RETINA: THE CONTROL OF PHOTORECEPTOR CELL FATE
Andrew Tomlinson, Principal Investigator
Columbia University Health Sciences, Columbia University Medical Center, New York, Ny 10032-3702
Grant 5R01EY012536-11 from National Eye Institute
Abstract: Understanding the signaling mechanisms that pattern and maintain the human eye are critically important to the medical community. A considerable amount of work is directed to understanding the pattern formation that occurs in the vertebrate eye, with the mouse being the standard model organism. Although completely unexpected, over the last 10 years it has become increasingly evident that the fly eye shares many structural and patterning features with the vertebrate eye. Thus, the fly can be considered another model organism for studying vertebrate eye development. Work in this lab has examined how signals from the tissue directly surrounding fly retina induce peripheral specializations necessary for the functioning eye. Recently, the same phenomenon was shown to occur in the mouse, using the same class of signaling molecules. Here, Wnt signals from the tissue directly adjacent to the retina direct the formation of the ciliary body and the iris. Our goals here are to examine in fine detail the patterning mechanisms by which the peripheral specializations are produced in the fly eye. We will use fly genetics, molecular biology, histology and biochemistry to determine the exact nature of the signals released that organize the peripheral specializations. We will elucidate the genes or proteins that are specifically turned on in the peripheral regions, and how they interact to direct the differentiation of the specialized structures. The results accruing from this work can then be taken and examined in the mouse to further our general understanding of retinal differentiation and its implications for human disease and vision
Keywords: Animal Model; Animal Models and Related Studies; Bears; Biochemistry; Body Tissues; CAPS; Capsules; Cell Communication and Signaling; Cell Signaling; Cells; Cessation of life; Chemistry, Biological; Ciliary Body; Communities; DNA Molecular Biology; Death; Development; Diffuse; Dorsal; Eye; Eye Development; Eyeball; Flies; Genes; Genetic; Genetic Screening; Goals; Head; Histology; Human; Human, General; Intracellular Communication and Signaling; Iris; Iris (Eye); Light; Mammals, Mice; Man (Taxonomy); Man, Modern; Medical; Mice; Modeling; Molecular Biology; Murine; Mus; Nature; Pattern; Pattern Formation; Peripheral; Photoradiation; Photoreceptor Cell; Photoreceptors; Photosensitive Cell; Pigments; Process; Programs (PT); Programs [Publication Type]; Proteins; Retina; Retinal; Role; Series; Sight; Signal Transduction; Signal Transduction Systems; Signaling; Signaling Molecule; Specific qualifier value; Specified; Structure; Testing; Thick; Thickness; Time; Tissues; Ursidae; Ursidae Family; Vision; Visual Receptor; Visual System; Visual system structure; Work; base; biological signal transduction; capsule (pharmacologic); cell killing; design; designing; eye morphogenesis; fly; gene product; human disease; model organism; ocular development; polarized light; programs; response; social role; transcription factor
Project start date: 1999-05-01
Project end date: 2012-03-31
Budget start date: 1-APR-2010
Budget end date: 31-MAR-2011
5R01EY012536-11 (2010): $398475
5R01EY012536-10 (2009): $509243
SIGNALING SPECIFICITY IN DROSOPHILA SERPENTINE RECEPTORS
Andrew Tomlinson, Assistant Professor
Genetics And Developmentcolumbia University Health Sciences
columbia University Medical Center
new York, Ny 100323702
Grant 1R01GM057043-01 from National Institute Of General Medical Sciences IRG: CBY
Abstract: hopes to increase understanding of the Hh and Wg signaling pathways by elucidating mechanisms about how the known components work and will identify new components in these pathways. Aim 1 will test the proposed model for Hh signaling, will map the domain of Smoothened that confers sensitivity to Ptc, and will test specificity of activating downstream components. Aim 2 will test the specific hypothesis that the serpentine receptors activate heterotrimeric G proteins. Aim 3 will use an elegant genetic screen to identify new genes in the Wg signaling pathway
Keywords: biological signal transduction, gene expression, receptor expression, receptor sensitivity G protein, genetic mapping Drosophilidae, chimeric protein
Project start date: 1998-01-01
Project end date: 2002-12-31
1R01GM057043-01 (1998): $255461
Signaling Specificity Of Drosophila Serpentine Receptors
Andrew Tomlinson, Professor
Genetics And Developmentcolumbia University Health Sciences
Grant 2R01GM057043-10A1 from National Institute Of General Medical Sciences IRG: DEV2
Abstract: Cellular polarization underlies many critical biological phenomena in wound healing, cells migrate to the site of lesion; neurons project axons that navigate to distant targets; and in the immune response, cells move to engulf invading pathogens. All these behaviors are mediated by the polarization of the cytoskeleton in response to external cues. A closely related phenomenon is called planar cell polarity (PCP). Here, cells arrayed in epithelia coordinately polarize so that all cells project their cuticular secretions in the same direction. Bird feathers, mammalian hairs and fish scales exemplify this phenomenon. This application is directed to understand how PCP is established. Drosophila is a model experimental organism in which PCP can be effectively investigated. Each cell uses a serpentine receptor called Frizzled (Fz) to decode an external gradient to direct its polarization. Serpentine receptors are typically transduced by trimeric G proteins, and the focus of this application is to understand the roles played by the fly G1o (and other PCP proteins) in Fz transduction and the organization of the cytoskeleton. We will use genetic, molecular and biochemical techniques to determine the exact relationship between Frizzled and G1o, and identify the proteins downstream of G1o in the transduction pathway. These studies will elucidate the mechanisms by which cells decode gradients, polarize their cytoskeletons, and communicate their actions to neighbors. Polarization of the cytoskeleton within cells is required for many critical bodily processes such as wound healing, formation of nerve connections, and the eradication of infection. A field of cells can coordinately organize their polarizations, as demonstrated by the organization of the cilliary bundles of the inner ear that permit us to hear sound. This application is designed to study planar cell polarity in fruit flies, to understand how cells can polarize and coordinate those polarizations in larger scale structures
Project start date: 1998-01-01
Project end date: 2013-01-31
2R01GM057043-06A2 (2004): $299909
RETINA--THE CONTROL OF PHOTORECEPTOR CELL FATE
Andrew Tomlinson, Assistant Professor
Genetics And Developmentcolumbia University Health Sciences
columbia University Medical Center
new York, Ny 100323702
Grant 5R01EY012536-03 from National Eye Institute IRG: VISC
Abstract: Adapted from applicant´s ) Patterning of the fly retina starts as the morphogenetic furrow sweeps through the eye imaginal disc. Successive waves of activation of the Ras pathway recruit the photoreceptors that form the ommatidia. However, the ommatidia are not all identical and later patterning events add at least two new features to the eye one is to define the type of inner photoreceptors that are involved in detection of colored or polarized light. Another is to create chirality to the ommatidium that is essential for the correct projection pattern of the photoreceptors to the neural cartridges in the optic lobe. This new application offers to test the mechanisms underlying these two events and in particular the role of wnt´s
Keywords: cellular polarity, compound eye, developmental neurobiology, genetic regulation, histogenesis, retina, visual photoreceptor biological signal transduction, cell differentiation, color vision, developmental genetics, gene expression Drosophilidae, alternatives to animals in research
Project start date: 1999-05-01
Project end date: 2003-04-30
5R01EY012536-03 (2001): $257571
5R01EY012536-02 (2000): $250067
1R01EY012536-01 (1999): $254783
Retina: The Control Of Photoreceptor Cell Fate
Andrew Tomlinson, Professor
Columbia University Health Sciences Columbia University Medical Center New York, Ny 100323702
Grant 5R01EY012536-08 from National Eye Institute IRG: ZRG1
Abstract: A critical question in retinal development is how different photoreceptor types are specified and positioned within a retina. The Drosophila eye is a valuable model system with which to address this question. The fly eye is a compound aggregate of many hundred sub-units called ommatidia. Within each ommatidium there are distinct photoreceptor types and ommatidia occur as different classes containing varying photoreceptor types. The photoreceptor types differ by their opsin expressions, their axonal projections, and their positions within the ommatidia. The major questions we are addressing here are (i) how the photoreceptors within each ommatidium are uniquely specified? (ii) How the different types of ommatidia are specified? (1) Specification of the R7 photoreceptor The UV sensitive photoreceptor in each ommatidium is the R7 cell. Signals from differentiating photoreceptors that contact the presumptive R7 and activate two distinct intracellular signals within the cell - the Ras and Notch (N) pathways. We wish to understand how these two pathways interact to specify the R7 cell. Do they act combinatorially to provide the R7 precursor with a unique developmental cue, or do they act in a different manner? For example could N pathway activation allow the activation of the Ras pathway and have no other function? Once these questions are answered we will examine the nature of the molecular interaction, and or integration of the two pathways. (2) Specification of asymmetry within the ommatidia The photoreceptors in each ommatidium are arrayed in an asymmetric manner that is critically related to the optical properties of the eye. Ommatidia decode graded information in the retina to establish an initial asymmetry that is then communicated to the other cells of the ommatidium. The questions here are how the graded information is established, and how it is decoded and communicated to all cells of the unit. (3) The specification of the dorsal rim The dorsal rim ommatidia are polarized light detector cells found in the dorsal extreme of the eye and contain specializations of the R7 and R8 cells. Signals emanating from the neighboring head tissue induce these ommatidia in only dorsal tissues. We wish to understand how signals from the head tissue organize the dorsal rim ommatidia and other associated retinal specializations.
Keywords: cell population study, compound eye, developmental genetics, developmental neurobiology, neural information processing, retina, visual photoreceptor, Drosophilidae
Project start date: 1999-05-01
Project end date: 2008-03-31
5R01EY012536-08 (2007): $354091
5R01EY012536-07 (2006): $379993
Sponsored Links Excellgen http://Excellgen.com
5R01EY012536-06 (2005): $388640
2R01EY012536-05A1 (2004): $388159