Excitotoxicity, which is a major cause of neurodegeneration in brain ischemia, can also activate neuroprotective pathways. A frequently suggested neuroprotective cascade involves the activation of the transcription factor CREB by its phosphorylation, but on its own this mode of CREB activation is promiscuous. We aim to elucidate the specific mechanism of CREB activation in excitotoxicity-induced neuroprotection, focusing on three suggested models: CREB phosphorylation by calcium-activated kinases in the cytoplasm or nucleus, and the activation of CREB by CRTC (an important cofactor). Using a C. elegans model of excitotoxicity, we demonstrate that CREB’s neuroprotective effect is mainly seen in neurons exposed to a moderate insult. Surprisingly, we find that CREB’s effect does not depend on the classic phosphorylation-activator CaMKK or the phosphorylation-dependent cofactor CBP. Instead, we find that the neuroprotective function of CREB in excitotoxicity depends on its cofactor CRTC/crtc-1 and its upstream regulators. Discovering the exact mechanism of CREB activation that is important for excitotoxic neuroprotection and examining CREB-mediated regulation of conserved neuroprotective genes may allow us to find candidate targets for future therapeutic interventions in brain ischemia.
","abstract_html":"<p>Excitotoxicity, which is a major cause of neurodegeneration in brain ischemia, can also activate neuroprotective pathways. A frequently suggested neuroprotective cascade involves the activation of the transcription factor CREB by its phosphorylation, but on its own this mode of CREB activation is promiscuous. We aim to elucidate the specific mechanism of CREB activation in excitotoxicity-induced neuroprotection, focusing on three suggested models: CREB phosphorylation by calcium-activated kinases in the cytoplasm or nucleus, and the activation of CREB by CRTC (an important cofactor). Using a <em>C. elegans</em> model of excitotoxicity, we demonstrate that CREB’s neuroprotective effect is mainly seen in neurons exposed to a moderate insult. Surprisingly, we find that CREB’s effect does not depend on the classic phosphorylation-activator CaMKK or the phosphorylation-dependent cofactor CBP. Instead, we find that the neuroprotective function of CREB in excitotoxicity depends on its cofactor CRTC/<em>crtc-1</em> and its upstream regulators. Discovering the exact mechanism of CREB activation that is important for excitotoxic neuroprotection and examining CREB-mediated regulation of conserved neuroprotective genes may allow us to find candidate targets for future therapeutic interventions in brain ischemia.</p>","abstract_has_math":false,"creators":["Feldmann, K. Genevieve"],"institution":"The Graduate School and University Center of The City University of New York","degree_name":"Doctor of Philosophy","degree_level":"Doctoral","degree_discipline":"Biology","degree_department":null,"school":null,"contributors":[],"advisors":["Itzhak Mano"],"committee_chairs":[],"committee_members":["Jonathan Levitt","Andreas Kottmann","Monica Driscoll","Shai Shaham","Chris Li"],"year":2018,"date_issued":"2018-05-01T07:00:00Z","date_published":"2018-05-01T07:00:00Z","updated_at":"2026-07-24T01:59:54Z","subjects":["Molecular and Cellular Neuroscience","Neuroscience and Neurobiology","Neuroscience","Excitotoxicity","Neuroprotection","CREB"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://academicworks.cuny.edu/gc_etds/2590","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Itzhak Mano"]},{"key":"dc:contributor.committeemember","label":"Committee Member","values":["Jonathan Levitt","Andreas Kottmann","Monica Driscoll","Shai Shaham","Chris Li"]},{"key":"dc:creator","label":"Author","values":["Feldmann, K. Genevieve"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2018-10-31T07:00:00Z"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Biology"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Doctoral"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy"]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["The Graduate School and University Center of The City University of New York"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Molecular and Cellular Neuroscience","Neuroscience and Neurobiology","Neuroscience","Excitotoxicity","Neuroprotection","CREB"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://academicworks.cuny.edu/gc_etds/2590"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Excitotoxicity, which is a major cause of neurodegeneration in brain ischemia, can also activate neuroprotective pathways. A frequently suggested neuroprotective cascade involves the activation of the transcription factor CREB by its phosphorylation, but on its own this mode of CREB activation is promiscuous. We aim to elucidate the specific mechanism of CREB activation in excitotoxicity-induced neuroprotection, focusing on three suggested models: CREB phosphorylation by calcium-activated kinases in the cytoplasm or nucleus, and the activation of CREB by CRTC (an important cofactor). Using a C. elegans model of excitotoxicity, we demonstrate that CREB’s neuroprotective effect is mainly seen in neurons exposed to a moderate insult. Surprisingly, we find that CREB’s effect does not depend on the classic phosphorylation-activator CaMKK or the phosphorylation-dependent cofactor CBP. Instead, we find that the neuroprotective function of CREB in excitotoxicity depends on its cofactor CRTC/crtc-1 and its upstream regulators. Discovering the exact mechanism of CREB activation that is important for excitotoxic neuroprotection and examining CREB-mediated regulation of conserved neuroprotective genes may allow us to find candidate targets for future therapeutic interventions in brain ischemia.
"]},{"key":"dc:title","label":"Title","values":["Non-canonical Activation of CREB/crh-1 Mediates Neuroprotection in a Caenorhabditis elegans Model of Excitotoxic Necrosis"]}]}],"canonical_facts":{"dc:contributor.advisor":["Itzhak Mano"],"dc:contributor.committeemember":["Jonathan Levitt","Andreas Kottmann","Monica Driscoll","Shai Shaham","Chris Li"],"dc:creator":["Feldmann, K. Genevieve"],"dc:date.available":["2018-10-31T07:00:00Z"],"dc:description.abstract":["Excitotoxicity, which is a major cause of neurodegeneration in brain ischemia, can also activate neuroprotective pathways. A frequently suggested neuroprotective cascade involves the activation of the transcription factor CREB by its phosphorylation, but on its own this mode of CREB activation is promiscuous. We aim to elucidate the specific mechanism of CREB activation in excitotoxicity-induced neuroprotection, focusing on three suggested models: CREB phosphorylation by calcium-activated kinases in the cytoplasm or nucleus, and the activation of CREB by CRTC (an important cofactor). Using a C. elegans model of excitotoxicity, we demonstrate that CREB’s neuroprotective effect is mainly seen in neurons exposed to a moderate insult. Surprisingly, we find that CREB’s effect does not depend on the classic phosphorylation-activator CaMKK or the phosphorylation-dependent cofactor CBP. Instead, we find that the neuroprotective function of CREB in excitotoxicity depends on its cofactor CRTC/crtc-1 and its upstream regulators. Discovering the exact mechanism of CREB activation that is important for excitotoxic neuroprotection and examining CREB-mediated regulation of conserved neuroprotective genes may allow us to find candidate targets for future therapeutic interventions in brain ischemia.
"],"dc:identifier":["https://academicworks.cuny.edu/gc_etds/2590"],"dc:subject":["Molecular and Cellular Neuroscience","Neuroscience and Neurobiology","Neuroscience","Excitotoxicity","Neuroprotection","CREB"],"dc:title":["Non-canonical Activation of CREB/crh-1 Mediates Neuroprotection in a Caenorhabditis elegans Model of Excitotoxic Necrosis"],"thesis:degree_discipline":["Biology"],"thesis:degree_level":["Doctoral"],"thesis:degree_name":["Doctor of Philosophy"],"thesis:institution_name":["The Graduate School and University Center of The City University of New York"]},"updated_at":"2026-07-24T01:59:54Z"}