1986 — 1988 |
Dodd, Jane |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Synaptic Mechanisms Underlying Sensory Transduction @ Columbia Univ New York Morningside
The main aim of this project is to provide a clearer understanding of the cellular and molecular events that are responsible for the transduction of sensory stimuli at the peripheral terminals of cutaneous afferent neurons. Several classes of cutaneous afferent neurons have been defined physiologically and, in many instances, the receptive properties of these neurons are correlated with morphological specializations of the peripheral endings. However, the mechanisms of transmission of information between specialized transduction cells and primary sensory endings remain unclear. Electrophysiological and immunological methods will be used to examine chemical transmission and cellular interactions at synaptic sites between two classes of transduction cell and their sensory innervation. These are the Merkel cell-sensory neuron junction and the junction between the taste bud receptor cell and its gustatory innervation. Immunological techniques will be used to identify and purify Merkel cells and taste buds and to maintain these cells in dissociated tissue culture. The biochemical, cytochemical and membrane properties of these cells will be characterized and compared with the properties of these cells in situ. Receptor cells will be grown in co-culture with appropriate classes of primary sensory neurons obtained from the dorsal root ganglion or the trigeminal ganglion, and identified using monoclonal antibodies that react with cell-surface antigens that are expressed selectively on each cell type. Pharmacological agents will be used to provide information on the identity of the transmitters released at the transduction cell-sensory neuron synapse. Intracellular recording will be used to monitor the sensitivity of sensory neurons to transmitters released from identified transduction cells. Similar approaches will be used to examine reciprocal actions on transduction cells of chemical mediators released from sensory neuron terminals.
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0.939 |
1989 — 1993 |
Dodd, Jane |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Axon Guidance At An Intermediate Target
The aim of this research project is to determine the cellular and molecular events that underlie the guidance of axons within the developing mammalian central nervous system. Dr Dodd has identified an intermediate target in the trajectory of a class of commissural neurons that appears to play a pivotal role in their guidance within the embryonic rat spinal cord. This structure, termed the floor plate, consists of a set of specialized epithelial cells. Although intermediate targets have been described in invertebrates they have not previously been observed in vertebrates. The effects of the floor plate on the morphology of commissural growth cones will be examined. In an EM study, floor plate.commissural growth cone contacts for morphological evidence of cellular communication through specialized junctions will be examined. In addition, the surface properties of floor plate cells will be characterized using immunochemical methods and the function of these molecules in floor plate/growth cone adhesive interactions that may be important for guidance at the midline will be examined. Many of the mechanisms that have been hypothesized to account for pathfinding by developing axons as they extend towards their final targets are based on experiments performed in invertebrates or in the peripheral nervous system of vertebrates. The studies described here will provide new information about the guidance of developing axons within the mammalian central nervous system and already suggest emerging parallels in the strategies and mechanisms by which neuronal projections are established in vertebrates and invertebrates.
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1 |
1990 — 2004 |
Dodd, Jane |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Axon Guidance in the Spinal Cord @ Columbia University Health Sciences
The goal of this work is to determine the cellular and molecular events that underlie the guidance of axons within the developing CNS. The development of the earliest commissural axon trajectory in the embryonic rat spinal cord provides an accessible model system in which to study the cues that guide CNS axonal projections. Commissural axons initially project circumferentially, away from the dorsal midline and close to the lateral edge of the spinal cord. The path of this axonal migration may be regulated by signals from the dorsal midline structure, the roof plate, and constrained laterally by an extracellular matrix component, the laminin-heparan sulphate proteoglycan complex. Commissural axons extend towards and across the ventral midline but then abruptly change their direction of extension, turning through 90 degrees to project longitudinally and rostrally within the ventral funiculus. The axonal turn occurs coincident with the contralateral boundary of a group of cells, known as the floor plate, that spans the ventral midline. The turn is disrupted in embryos in which the floor plate is absent, suggesting that navigational information is associated with the floor plate itself. However, in addition to floor plate cells and their underlying basal lamina, two other potential sources of guidance cues are: axons crossing from the contralateral side and neuroepithelium lateral to the floor plate. The cue that directs longitudinal growth in a rostral direction may be localized within the spinal cord or may emanate from a supraspinal source. In vitro preparations of spinal cord have been established that permit visualization and experimental perturbation of the commissural projection as it develops. Ectopic presentation and selective ablation of distinct cell types and antibody perturbation of cell surface molecules will be used to examine whether the roof plate regulates the direction of circumferential growth, which of the cells contacted by commissural growth cones are required for pathfinding at the midline and whether the functions of these cell types are mediated by any of several identified molecules. These experiments will provide information about the range of cues that together shape an axonal projection and the role of intermediate targets in axon guidance. Despite the prevalence and importance of projection paths in the CNS there is currently no information on the cues that are likely to operate initially to direct longitudinal growth. The experiments described above therefore have important implications for our understanding of the development of projection pathways throughout the CNS.
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1 |
1993 — 1997 |
Dodd, Jane |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Control of Floor Plate Induction by Axial Mesoderm
The goal of the experiments to be described in this proposal is to elucidate the cellular and molecular events underlying the induction of the floor plate by the notochord. The floor plate is a specialized set of neuroepithelial cells located at the ventral midline of the embryonic spinal cord. The floor plate appears to be responsible for the differentiation and organization of neurons within the ventral spinal cord and, at later stages of development, plays a pivotal role in the guidance of axons within the spinal cord. We have previously shown that the differentiation of functional and antigenic properties that are specific to the floor plate is dependent on an inductive signal from the underlying notochord. The experiments described here use a simple assay system to measure the induction of floor plate-specific gene expression in cells of the lateral neural plate that would not normally give rise to floor plate. This assay will be used to examine the developmental expression pattern and biochemical properties of the notochord-derived signal and as a detection method in the identification of the activity. We will use an expression cloning approach to identify cDNAs that encode the floor plate-inducing activity. In the longer term, the goal is to understand the mechanisms by which neuroepithelial cells respond to the notochordal signal and initiate a program of floor plate differentiation. The identification of a notochord-derived floor plate-inducing signal and the elucidation of its mechanisms of action will be an important step in the understanding of early inductive processes and in the differentiation and organization of the early neural tube.
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0.954 |
1993 — 1997 |
Dodd, Jane |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Core--Antibody
monoclonal antibody; biomedical facility;
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0.954 |
1998 — 2002 |
Dodd, Jane |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Induction and Patterning of Neural Tube Ventral Midline
The overall goal of this work is to understand the molecular and cellular basis for the acquisition of distinct cell fates along the rostrocaudal axis of the developing neural tube. The focus of the work is the differentiation of the ventral midline cell group which, in caudal regions, comprises the floor plate and, more rostrally, spans the ventral midline of the rostral forebrain. These cells play major roles in the patterning of cells and axons within the dorsoventral axis of the neural tube but the properties of the ventral cell groups differ at different rostrocaudal positions along the axis. In caudal regions, the floor plate is induce by signals from the underlying axial mesoderm cells of the notochord. In rostral diencephalon, the induction of the midline cells appears to be controlled by different axial mesoderm, the prechordal mesoderm. Furthermore, although the signalling molecule, Sonic Hedgehog, mediates the induction and differentiation of the floor plate, in the rostral forebrain a second signalling factor, BMP7, is required to act in concert with Sonic Hedgehog, apparently sensitizing neural cells to Sonic Hedgehog signalling, to induce cells with rostral character. The aims of this proposal are to examine in detail the role of BMP7 in rostralization of the ventral midline and to determine the mechanisms underlying this novel interaction between BMP7 and Sonic Hedgehog. The main experimental tool will be in vitro explant assays, which permit the response of neural plate tissue to signals from mesoderm to be monitored and manipulated. These will be used in conjunction with mice in which genes encoding components of the proposed pathways of differentiation have been functionally inactivated. Experiments will trace the site of action of BMP7 and will investigate potential mechanisms of its action on neural tissue. In addition, we will determine whether related transcription factors mediate the initial events in response to Sonic Hedgehog in distinct populations of midline cells. The possibility that additional agents are involved in the rostrocaudal patterning of ventral midline regions intermediate between rostral forebrain and caudal floor plate will also be examined. The distribution and role of BMP function-blocking proteins will be studied. Together, these experiments will lead to an understanding of the mechanisms underling the differential patterning and properties of the floor plate and ventral midline cells of the rostral forebrain. In addition, however, they will provide insight more generally into rostrocaudal patterning of neural tissue, revealing mechanisms and candidate molecules that are involved in defining this axis of the neural plate.
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0.954 |
2015 — 2016 |
Dodd, Jane |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Trans-Synaptic Tracing of Developing Somatosensory Circuits @ Columbia University Health Sciences
? DESCRIPTION (provided by applicant): Summary A major issue in understanding the development of central somatosensory circuitry is the lack of available markers that permit observation of the paths taken and choices made by individual classes of spinal sensory neurons between initial specification of neural identity, and the establishment of central connections. For this reason it also remains unclear which embryonic subsets of dorsal spinal neuron become those that subserve each distinct somatosensory function. Although many subsets of dorsal horn neuron have been delineated during differentiation and early migratory phases of development, there is a fundamental need to bridge the period when neurons can be identified according to their transcriptional signature and when they can be identified according to their functional circuitry. Methods are required that permit visualization of the synaptic connections between functional classes of DRG neurons and individual classes of dorsal horn neuron and allow us to determine where and how those dorsal horn neurons project centrally during development and in the adult. The recent demonstration that attenuated rabies virus can be directed to specific cell types in the mature nervous system and travel transsynaptically from sensory neurons in the periphery into target central neurons, provides a way to explore the development of the central somatosensory system, defining functional connections through the establishment of synapses, permitting the assignment of function to embryonically identified neurons and conferring a marking technique that allows visualization of the central paths forged y individual classes of dorsal horn neuron. The object of the research in this R21 is to develop methodology that will permit selective anterograde and retrograde transsynaptic tracing of developing somatosensory circuitry during development and to establish the techniques for general use in developing systems.
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1 |
2021 |
Dodd, Jane Mason, Carol A. (co-PI) [⬀] |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Linking the Molecular Logic of Sensory Neuron Diversity and Somatosensory Circuitry in Mouse Spinal Cord: Development of Novel Tools For Viral Tracing and 3d Analysis @ Columbia University Health Sciences
Project Summary/Abstract Sensory neurons in the dorsal spinal cord (dINs) represent the first site in the CNS to receive somatosensory information from the periphery and are a crucial component in sensorimotor circuits that control posture and behavior. Defining the developmental principles of somatosensory circuit formation and the molecular identity of neurons that serve specific sensory functions is key to our understanding of the logic of sensorimotor integration and for strategic interventions following injury or disease. All dINs arise from a small array of molecularly defined embryonic cell populations, but markers are expressed only transiently and how these early neurons diversify and integrate into sensory circuits serving distinct sensory modalities in the mature animal remains largely unknown. There is an urgent need for genetic access to express tracers and to manipulate individual classes of developing dINs as they emerge during the embryonic period but establish circuits postnatally. Here, we will generate for the first time, mice that bridge the gap between early identity and mature function by providing access selectively to one population of dINs, called dI1s, throughout development. We will create mouse lines to introduce anterograde and retrograde viral tracers to reveal and map the synaptic targets of dI1s in brain and spinal cord, and to identify input neurons to dI1s, in DRG, brain and spinal cord. These lines will extend temporal genetic access selectively to developing dI1s into postnatal stages, by, first, a Cre-dependent Cre approach, permitting access by Cre-dependent axonal and synaptic tracers, and second, mice that express the proteins required for transsynaptic tracing using rabies virus. We will also develop platforms to analyze efficiently the anatomy and connectivity of the circuitry. Furthermore, we will create a widely needed 3D spinal cord atlas for assessment of neuronal identity and mapping circuitry. To understand the programs that regulate dI1 development, we will also identify and follow dynamic changes of transcriptional signatures in dI1s throughout embryonic and postnatal ontogeny by single cell RNA sequencing. The tools established in the proposed experiments and analyses will be applicable to all dIN subsets and will contribute both resources and information to the field, and provide a template for manipulation and functional analysis of somatosensory pathways in health and in disease.
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