Area:
Visual System, lncRNAs
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High-probability grants
According to our matching algorithm, Brian S. Clark is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2014 — 2016 |
Clark, Brian S Clark, Brian S [⬀] |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Regulation of Retinal Progenitor Cell Competence by Long Noncoding Rnas @ Johns Hopkins University
DESCRIPTION (provided by applicant): The generation of neuronal subtype diversity is controlled by the progression of multi-potent neural progenitors through a series of developmental competence states in which they successively lose and often also acquire the ability to generate different cell types. Recent studies have clearly shown that retinal progenitor cell (RPC) competence is controlled cell autonomously, with competence changes hypothesized to occur by temporally dynamic regulation of transcription factor activity. Despite extensive RNA expression profiling of the developing mouse retina, only a few RPC-expressed transcription factors have been identified whose expression tracks with changes in developmental competence. This suggests that other genes that regulate transcription factor activity may ultimately play a central role in regulating RPC competence. The mouse genome contains over 10,000 long noncoding RNAs (lncRNAs), some of which are known to regulate transcription factor activity. Using RNA-Seq analysis, we have identified over 100 lncRNAs that are differentially expressed between early and late-stage RPCs, and we hypothesize that a subset of these will play a critical role in regulating RPC competence. To test this hypothesis, evolutionarily conserved, lncRNAs that display dynamic expression within progenitors have been identified from mouse retinas. Cellular expression patterns of candidate lncRNAs in developing retina will be examined through in situ hybridization and quantitative RT-PCR experiments. The role of candidate lncRNAs in regulation of RPC competence will then be tested using both overexpression and knockdown in developing retina and genetic approaches. Finally, to determine the molecular mechanism by which lncRNAs regulate RPC competence, we will use protein microarrays and RNA immunoprecipitation to identify proteins that directly interact with candidate lncRNAs, and in turn determine whether overexpression or knockdown of these protein-coding genes regulates RPC competence. These studies will improve our understanding of long noncoding RNA function and provide important insight into mechanisms regulating neural progenitor competence. Furthermore, since approximately one-third of all phenotype-associated polymorphisms identified in genome-wide association studies map to non-protein coding regions of the genome, further characterization of lncRNA function may prove critical in understanding the pathology of multiple genetic diseases.
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2017 — 2021 |
Clark, Brian S [⬀] |
K99Activity Code Description: To support the initial phase of a Career/Research Transition award program that provides 1-2 years of mentored support for highly motivated, advanced postdoctoral research scientists. 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. |
Identification of the Molecular Mechanisms Mediating Intrinsic Control of Retinal Progenitor Competence
The specification of retinal cell types from a common, multi-potent progenitor cell occurs in an overlapping temporal birth order. Previous studies have concluded that the selection of an individual progenitor to undergo a terminal division, whereby at least one daughter cell exits the cell cycle, is largely controlled cell autonomously. Therefore, it has been hypothesized that changes in the ability of retinal progenitors to differentiate as specific retinal cell types results from either an inherent heterogeneity of progenitors resulting in lineage biases or global changes in gene expression across development that correspond to changes in cell fate specification. In order to test these hypotheses, I previously characterized the transcript expression of individual progenitors across retinal development using single-cell RNA-sequencing. These experiments support a model in which retinal progenitors are not lineage restricted but exhibit global changes in gene expression corresponding to progenitor cell maturation across development. Additionally, the profiling of retinal progenitor transcriptomes has enabled us to identify numerous candidate genes hypothesized to 1) regulate the proliferative potential of retinal progenitors 2) confer maturation of retinal progenitors across developmental time and 3) control the temporal specification of individual retinal cell fates. As proof in principal, we showed that the late progenitor cell enriched NFI transcription factors regulate both proliferative quiescence and generation of late-born cell types. The goal of these continued studies is to identify the mechanisms by which retinal progenitor cells are selected to undergo a terminal division and to determine if these candidate genes also impart biases in specification of individual retinal cell fates. The function of candidate genes in the regulation of cell cycle exit and cell fate specification will be determined through gain/loss-of-function experiments within the developing retina through both in vivo and ex vivo electroporations and genetic models. Mechanistic insights into candidate gene function will be performed through protein arrays to identify interacting proteins, ChIRP-seq/ChIP-seq to examine the RNA-DNA or protein-DNA interactions, respectively, and through reporter assays to identify the temporal activity of cis-regulatory elements. These studies will provide import insights into the genes and mechanisms regulating temporal cell fate specification within the developing retina, information vital to understanding the pathogenesis of retinal dystrophies and for understanding treatment of these diseases.
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