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High-probability grants
According to our matching algorithm, Thomas M. Coate is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2014 — 2017 |
Coate, Thomas M |
R00Activity Code Description: To support the second phase of a Career/Research Transition award program that provides 1 -3 years of independent research support (R00) contingent on securing an independent research position. Award recipients will be expected to compete successfully for independent R01 support from the NIH during the R00 research transition award period. |
Wiring of Spiral Ganglion Neurons and Auditory Hair Cells by Secreted Semaphorins
The establishment and maintenance of spiral ganglion neuron (SGN) connections with hair cells in the cochlea is critical to auditory function, and the disruption of these connections is both a well-recognized consequence of sensorineural hearing loss, and a cause of diminished cochlear implant performance. Despite the importance of these connections, the mechanisms required for SGN axon guidance and synaptogenesis are largely unknown. The long-term goal of this research is to define the mechanisms responsible for auditory nervous system development, so that improved therapies can be developed to treat hearing loss in humans. The results from the research outlined in this application will define how class-3 Semaphorins (Sema3s), a large family of secreted factors that activate Neuropilin/Plexin (Nrp/Plxn) coreceptors on growing axons, are essential for SGN axon guidance decisions. Conceptually, the proposed research is innovative because it will provide the first in-depth analysis of hearing loss caused by SGN axon guidance defects, as there is little known about how the elaboration of SGN fibers within the cochlear duct con-elates with audiological assessments. The proposed research is technically innovative because a mouse model that allows the labeling, visualization and analyses of SGN-hair cell interactions in real time will be used. The function of specific class-3 Semaphorins that are expressed in the cochlea will be defined. Gain-of-function adenovirus infection experiments, and loss-of-function mouse models, will be used to test the hypothesis that Sema3C attracts SGNs and that Sema3A sorts different populations of SGNs. In order to transmit a signal intracellularly, Nrps must bind to Plexin co-receptors. Distinct populations of SGNs differentially express PlexinA3, thus the function of PlexlnA3 will be determined. Using pharmacology, mouse models, and protein truncation experiments, the hypothesis that PlexinA3 activation in different populations of SGNs targets them to specific populations of hair cells will be tested. This contribution of this research will be significant because it will define one of the first molecular signaling pathways to contribute to the development of the complex afferent innervation pattern within the mammalian auditory system.
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2018 — 2021 |
Coate, Thomas M |
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. |
Cellular and Molecular Mechanisms of Cochlear Innervation
PROJECT SUMMARY Hearing function depends on precise connectivity patterns of spiral ganglion neurons (SGNs), olivocochlear efferents, and hair cells in the cochlea. Deficits in these connections underlie hearing impairment and the efficacy of cochlear implants. The long-term goal of this research is to define the mechanisms responsible for wiring events between neurons and hair cells in the cochlea, so that improved therapies can be developed to treat hearing loss in humans. Pou3f4 is a transcription factor expressed by otic mesenchyme cells in the cochlea and mutations in Pou3f4 cause human hearing loss. Loss of Pou3f4 in mouse models leads to morphological defects in otic mesenchyme and these models are known to be hearing impaired as a result of reduced endocochlear potential. We showed recently that Pou3f4 is critical in SGN axon guidance. But, we have a very limited understanding of how Pou3f4 controls auditory innervation mechanisms because the transcriptional targets of Pou3f4 in the cochlea are not well understood. This proposal seeks to determine the function of Pou3f4 in axon guidance, transcriptional regulation, and neuronal survival in the auditory system. Ephrins are cell-surface bound ligands that activate Ephs (receptor tyrosine kinases) to facilitate diverse forms of intercellular communication including axon guidance and synaptogenesis. Our preliminary data suggest that Pou3f4 regulates the expression of Ephrin genes in otic mesenchyme and that these are critical in hair cell wiring. Results from the proposed work will demonstrate how these Ephrin proteins control cochlear innervation and contribute innervation defects observed in Pou3f4 mutants. Results from our proposed work will also generate a comprehensive set of Pou3f4 transcriptional targets, which will include all possible factors involved in cochlear innervation. We have also found that otic mesenchyme cells express Pou3f4 into adulthood and that Pou3f4 null adults show a significant loss of SGNs. Thus, in these studies, we will also determine the mechanism(s) by which Pou3f4 normally mediates SGN survival. In this work, we will use a range of in vivo and in vitro techniques, innovative imaging approaches, and transcriptional profiling methods. The contribution of this research will be significant because it will determine how Pou3f4 and its targets contribute to the development and maintenance of the complex afferent innervation patterns within the mammalian auditory system. In addition, this work is expected to determine new guidance mechanisms required for appropriate auditory connectivity, thus it will complement ongoing work by others on neurotrophins, gene therapy, or cell replacement strategies.
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