2009 — 2011 |
Ben-Shahar, Yehuda |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
Chemosensory Roles For Epithelial Sodium Channels
DESCRIPTION (provided by applicant): Degenerin/ epithelial sodium channels (Deg/ENaC) are voltage-insensitive cationic channels that are widely expressed in epithelial and neuronal tissues. In mammals, several Deg/ENaC subunits are critical for maintaining sodium ionic gradient across epithelial barriers in different tissues. Several members of the family are also highly expressed in sensory neurons of various modalities. Yet, the physiological role of Deg/ENaC channels at the sensory level is still poorly defined. Heterologous expression studies suggest that Deg/ENaC channels can be activated by a variety of extracellular stimuli such as protons, peptides, proteases, and mechanical stretch. The Deg/ENaC family is exceptionally large in the genomes of Drosophila species;while only eight members of the family have been identified in mammals, the fly genome contains thirty independent Deg/ENaC genes. These data suggest that members of the Deg/ENaC family in the fruit fly are highly specialized. The Deg/ENaC subunit abundance in the fly genome presents an opportunity to use the power of Drosophila genetics to elucidate the sensory roles of specific Deg/ENaC ion channels, and hence gain new knowledge about the physiological roles of Deg/ENaC ion chanels in the peripheral nervous systm. This proposal is focused on characterizing one Deg/ENaC family member, aguesic (agu), which was identified as a channel highly enriched in gustatory-like neurons in the fly. Preliminary data suggest that agu has a role in courtship related behaviors. Aim 1 will test the hypotheses that agu-expressing cells are sex-specific and functionally distinct from the feeding related gustatory sensory system. Aim 2 will test the hypothesis that AGU functions as a chemoreceptor. Aim 3 will test the hypothesis that other agu-like Deg/ENaC subunits have chemosensory roles. Strategy will include development of genetic and transgenic tools, physiological measures of neuronal activation, and ectopic activation of sensory neurons to unravel the sensory roles of chemosensory-specific Deg/ENaC channels in Drosophila. Understanding the sensory physiological role for Deg/ENaC ion channels in the fruit fly model could reveal novel functions for these channels in a wide range of mammalian sensory modalities such as taste, pain, and nociception. PUBLIC HEALTH RELEVANCE: Animals use functionally diverse array of proteins to constantly extract information about their environment. This project examines the role of specific degenrin/ epithelial sodium channels and the sensory neurons expressing them in mediating chemosensory signals associated with social interactions.
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0.948 |
2013 — 2017 |
Ben-Shahar, Yehuda |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Icob: Mirnas and the Social Regulation of Behavioral Plasticity
Elaborate genetic networks drive complex phenotypes such as social behaviors. The recent sequencing of genomes of several social species such as the honey bee and the bumblebee provide powerful opportunities to study sociality in molecular terms. This collaborative project focuses on molecular mechanisms that contribute to the regulation of division of labor among social insects workers. Studies will investigate the role of microRNAs in regulating two systems of division of labor; age-dependent division of labor in highly social honey bees, and size-related division of labor in bumblebees. The first goal is to investigate the role of miRNAs in behavior by comparing changes in brain-enriched microRNAs that are associated with division of labor in both species. The second goal is to determine whether hormonal signals that affect division of labor in honey bees, but not bumblebees, are mediated via the action of honey bee specific microRNAs. The third goal is to establish causation between the action of conserved miRNAs and the regulation of behavioral plasticity by looking in the fruit fly, Drosophila. Both honey bees and bumblebees are economically important due to their unique roles as pollinators of diverse crops. The proposed studies will lead to a better understanding of the mechanisms that govern bee behavior in particular, and animal foraging behaviors in general.
These studies will also provide extensive training opportunities. High school and undergraduate students, including underrepresented minorities, will be trained in collecting behavioral, molecular, and physiological data, their analyses, and in scientific presentations at local and national meetings. Furthermore, this project will serve as an excellent mentorship opportunity for the postdoctoral fellow who will lead the studies. Finally, this international collaboration will foster research ties between American and Israeli research institutions, which will include reciprocal international training opportunities for personnel from both labs.
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0.948 |
2014 — 2015 |
Ben-Shahar, Yehuda |
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.) |
A Role For the Endogenous Sirna Pathway in Regulating Neuronal Excitability
DESCRIPTION (provided by applicant): In order to maintain functional ionic gradients across their membranes during physical and biological stresses, neurons need to adjust their electrical properties. Understanding how such physiological adjustments are made is important since disruptions in neuronal homeostasis have been implicated in various behavioral and neuronal pathologies, such as seizures and cognitive deficits, as well as in certain psychiatric conditions. Established models propose that the regulation of neuronal homeostasis requires changes in the relative abundances of potassium and sodium channels at the membrane. Yet, how these channels are regulated in response to environmental stresses such as heat is not well understood. This proposal investigates a novel posttranscriptional molecular mechanism for the regulation of neuronal homeostasis. Our proposal is based on our preliminary data, which demonstrate that pickpocket 29 (ppk29), a Drosophila Degenerin/epithelial sodium channel (DEG/ENaC), and seizure (sei), the sole fly homolog of the human Ether-alpha-go-go-Related Gene (hERG) potassium channel, are convergently transcribed from opposite DNA strands with their 3'UTRs complementing each other. Previous studies have indicated that mutations in sei cause sensitivity to heat induced seizures and paralysis due to hyperexcitability. In contrast, mutations in ppk29 lead to opposite neurophysiological and behavioral phenotypes that are consistent with a protection from heat induced seizures and paralysis. Furthermore, our data indicate that the 3'UTR of ppk29 regulates neuronal plasticity independent of its protein coding capacity. The unusual genetic architecture and the opposing neuronal and behavioral phenotypes mediated by these two functionally antagonistic channels led us to study the hypothesis that the mRNA of one ion channel can regulate the function of another opposing ion channel via the formation of 3'UTRs-dependent dsRNA leading to gene specific siRNAs, which act as a molecular regulatory mechanism underlying the homeostatic neuronal response to environmental stress.
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0.948 |
2017 — 2020 |
Robinson, Gene Duncan, Ian Ben-Shahar, Yehuda Raman, Baranidharan (co-PI) [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Neuronex Technology Hub: Advancing Neuronal and Genetic Approaches to Animal Behavior Research
Neuroscience is one of the most prominent areas of modern biomedical research, but its impact on other fields, particularly those related to environmental and organismal biology, has been limited. This is because an increasing proportion of neuroscience research has been concentrated on just a few "model" animal species, such as the mouse and fruit fly, for which powerful genetic tools have been developed to manipulate their genomes. This focus stands in stark contrast to the early days of neuroscience research, in which a broader sampling of biodiversity led to important discoveries. Prominent examples include the discovery of how neurons become activated in the squid and how long-term memory is established in a marine slug. The primary goal of this proposal is to increase the diversity of animal species that can be used to advance neuroscience research by developing and applying modern neurogenetic tools for observing and manipulating neuronal activity in any animal species. As a proof-of-principle, state-of-the-art tools are developed for the honey bee and the American grasshopper. In addition to having immediate impact on basic neuroscience, the project has impact on applied research, as these two selected species are important pests and pollinators, respectively. The new tools and research findings from the proposed work is disseminated to the research community via NSF-funded initiatives to increase species diversity in genetic studies, and national and international workshops. The dissemination efforts include the development of an annual intensive summer course at Washington University that entails both lectures and hands-on experiences for organismal biologists who are interested in incorporating modern neuroscience and genetic tools into their research programs. Additional educational and training opportunities served by the project include public neuroscience outreach efforts in the St. Louis region, training of postdoctoral fellows, as well as mentoring of graduate, undergraduate, and high school students in hypothesis-driven neuroscience research.
The lack of species diversity in modern neuroscience research restricts the applicability and interpretations of general neurobiological principles in the context of organismal, ecological, and evolutionary questions. Therefore, the primary goal of this proposal is to increase animal species diversity in systems and behavioral neuroscience research by enabling easy adoption of universal genetic and transgenic tools for monitoring and manipulating neuronal activity in any animal species, with a specific emphasis on insects. The proposed approach is comprised of two steps. First, Cas9/CRISPR-dependent genome editing is used to replace the non-essential gene white with a DNA cassette that includes an eye-specific red fluorescent protein (RFP) flanked by two directional phiC31-integrase attP sites, enabling rapid screening of both white eye-color and RFP expression as markers of successful germline transformation. Second, the efficient phiC31-Integrase reaction is used to replace the RFP cassette with a transgene of choice. As a proof-of-principle, transgenic lines that express the Ca2+ reporter GCaMP6 in defined neuronal populations in the honey bee Apis mellifera and the American grasshopper Schistocerca americana are generated and tested for feasibility. By enabling the use of modern genetic tools to enhance neuroscience research in these two economically important insect species, which also serve as important models for basic organismal biological research, the proposed project is likely to have broad impact relevant to diverse research fields, including agriculture, neuroethology, animal behavior, pest ecology, and behavioral neuroscience. This NeuroTechnology Hub award is part of the BRAIN Initiative and NSF's Understanding the Brain activities.
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0.948 |