[{"user_id":"8b945eb4-e2f2-11eb-945a-df72226e66a9","citation":{"chicago":"Schulz, Rouven. “Chimeric G Protein-Coupled Receptors Mimic Distinct Signaling Pathways and Modulate Microglia Function.” Institute of Science and Technology Austria, 2022. <a href=\"https://doi.org/10.15479/at:ista:11945\">https://doi.org/10.15479/at:ista:11945</a>.","ista":"Schulz R. 2022. Chimeric G protein-coupled receptors mimic distinct signaling pathways and modulate microglia function. Institute of Science and Technology Austria.","mla":"Schulz, Rouven. <i>Chimeric G Protein-Coupled Receptors Mimic Distinct Signaling Pathways and Modulate Microglia Function</i>. Institute of Science and Technology Austria, 2022, doi:<a href=\"https://doi.org/10.15479/at:ista:11945\">10.15479/at:ista:11945</a>.","apa":"Schulz, R. (2022). <i>Chimeric G protein-coupled receptors mimic distinct signaling pathways and modulate microglia function</i>. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/at:ista:11945\">https://doi.org/10.15479/at:ista:11945</a>","ama":"Schulz R. Chimeric G protein-coupled receptors mimic distinct signaling pathways and modulate microglia function. 2022. doi:<a href=\"https://doi.org/10.15479/at:ista:11945\">10.15479/at:ista:11945</a>","short":"R. Schulz, Chimeric G Protein-Coupled Receptors Mimic Distinct Signaling Pathways and Modulate Microglia Function, Institute of Science and Technology Austria, 2022.","ieee":"R. Schulz, “Chimeric G protein-coupled receptors mimic distinct signaling pathways and modulate microglia function,” Institute of Science and Technology Austria, 2022."},"language":[{"iso":"eng"}],"oa":1,"file":[{"file_size":28079331,"date_created":"2022-08-25T08:59:57Z","date_updated":"2022-08-25T08:59:57Z","creator":"rschulz","file_id":"11970","file_name":"Thesis_Rouven_Schulz_2022_final.pdf","success":1,"content_type":"application/pdf","access_level":"open_access","relation":"main_file","checksum":"61b1b666a210ff7cdd0e95ea75207a13"},{"relation":"source_file","checksum":"2b8f95ea1c134dbdb927b41b1dbeeeb5","file_name":"Thesis_Rouven_Schulz_2022_final.docx","access_level":"closed","content_type":"application/vnd.openxmlformats-officedocument.wordprocessingml.document","file_id":"11971","file_size":27226963,"date_created":"2022-08-25T09:00:11Z","creator":"rschulz","date_updated":"2022-08-25T09:33:31Z"}],"department":[{"_id":"GradSch"},{"_id":"SaSi"}],"month":"08","supervisor":[{"full_name":"Siegert, Sandra","id":"36ACD32E-F248-11E8-B48F-1D18A9856A87","last_name":"Siegert","orcid":"0000-0001-8635-0877","first_name":"Sandra"}],"publication_status":"published","publication_identifier":{"issn":["2663-337X"]},"file_date_updated":"2022-08-25T09:33:31Z","tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","short":"CC BY (4.0)"},"abstract":[{"text":"G protein-coupled receptors (GPCRs) respond to specific ligands and regulate multiple processes ranging from cell growth and immune responses to neuronal signal transmission. However, ligands for many GPCRs remain unknown, suffer from off-target effects or have poor bioavailability. Additional challenges exist to dissect cell-type specific responses when the same GPCR is expressed on several cell types within the body. Here, we overcome these limitations by engineering DREADD-based GPCR chimeras that selectively bind their agonist clozapine-N-oxide (CNO) and mimic a GPCR-of-interest in a desired cell type.\r\nWe validated our approach with β2-adrenergic receptor (β2AR/ADRB2) and show that our chimeric DREADD-β2AR triggers comparable responses on second messenger and kinase activity, post-translational modifications, and protein-protein interactions. Since β2AR is also enriched in microglia, which can drive inflammation in the central nervous system, we expressed chimeric DREADD-β2AR in primary microglia and successfully recapitulate β2AR-mediated filopodia formation through CNO stimulation. To dissect the role of selected GPCRs during microglial inflammation, we additionally generated DREADD-based chimeras for microglia-enriched GPR65 and GPR109A/HCAR2. In a microglia cell line, DREADD-β2AR and DREADD-GPR65 both modulated the inflammatory response with a similar profile as endogenously expressed β2AR, while DREADD-GPR109A showed no impact.\r\nOur DREADD-based approach provides the means to obtain mechanistic and functional insights into GPCR signaling on a cell-type specific level.","lang":"eng"}],"acknowledged_ssus":[{"_id":"Bio"},{"_id":"PreCl"},{"_id":"LifeSc"}],"has_accepted_license":"1","date_created":"2022-08-23T11:33:11Z","title":"Chimeric G protein-coupled receptors mimic distinct signaling pathways and modulate microglia function","oa_version":"Published Version","author":[{"orcid":"0000-0001-5297-733X","first_name":"Rouven","last_name":"Schulz","full_name":"Schulz, Rouven","id":"4C5E7B96-F248-11E8-B48F-1D18A9856A87"}],"day":"23","date_published":"2022-08-23T00:00:00Z","project":[{"_id":"267F75D8-B435-11E9-9278-68D0E5697425","name":"Modulating microglia through G protein-coupled receptor (GPCR) signaling"}],"status":"public","degree_awarded":"PhD","related_material":{"record":[{"relation":"dissertation_contains","status":"public","id":"11995"}]},"year":"2022","ddc":["570"],"page":"133","type":"dissertation","date_updated":"2023-08-03T13:02:26Z","_id":"11945","publisher":"Institute of Science and Technology Austria","doi":"10.15479/at:ista:11945","article_processing_charge":"No","alternative_title":["ISTA Thesis"]},{"type":"dissertation","_id":"12378","date_updated":"2023-08-04T09:40:37Z","publisher":"Institute of Science and Technology Austria","alternative_title":["ISTA Thesis"],"article_processing_charge":"No","doi":"10.15479/at:ista:12378","ddc":["570"],"page":"142","related_material":{"record":[{"status":"public","relation":"part_of_dissertation","id":"12244"}]},"year":"2022","date_published":"2022-11-11T00:00:00Z","ec_funded":1,"status":"public","project":[{"call_identifier":"H2020","name":"International IST Doctoral Program","grant_number":"665385","_id":"2564DBCA-B435-11E9-9278-68D0E5697425"}],"degree_awarded":"PhD","date_created":"2023-01-25T14:27:43Z","title":"MorphOMICs, a tool for mapping microglial morphology, reveals brain region- and sex-dependent phenotypes","oa_version":"Published Version","day":"11","author":[{"orcid":"0000-0001-9434-8902","first_name":"Gloria","last_name":"Colombo","id":"3483CF6C-F248-11E8-B48F-1D18A9856A87","full_name":"Colombo, Gloria"}],"file_date_updated":"2023-04-12T22:30:03Z","publication_status":"published","publication_identifier":{"issn":["2663-337X"]},"acknowledged_ssus":[{"_id":"PreCl"},{"_id":"Bio"},{"_id":"ScienComp"}],"abstract":[{"text":"Environmental cues influence the highly dynamic morphology of microglia. Strategies to \r\ncharacterize these changes usually involve user-selected morphometric features, which \r\npreclude the identification of a spectrum of context-dependent morphological phenotypes. \r\nHere, we develop MorphOMICs, a topological data analysis approach, which enables semi\u0002automatic mapping of microglial morphology into an atlas of cue-dependent phenotypes,\r\novercomes feature-selection bias and minimizes biological variability. \r\nFirst, with MorphOMICs we derive the morphological spectrum of microglia across seven \r\nbrain regions during postnatal development and in two distinct Alzheimer’s disease \r\ndegeneration mouse models. We uncover region-specific and sexually dimorphic\r\nmorphological trajectories, with females showing an earlier morphological shift than males in \r\nthe degenerating brain. Overall, we demonstrate that both long primary- and short terminal \r\nprocesses provide distinct insights to morphological phenotypes. Moreover, using machine \r\nlearning to map novel condition on the spectrum, we observe that microglia morphologies \r\nreflect a dose-dependent adaptation upon ketamine anesthesia and do not recover to control \r\nmorphologies.\r\nNext, we took advantage of MorphOMICs to build a high-resolution and layer-specific map of \r\nmicroglial morphological spectrum in the retina, covering postnatal development and rd10 \r\ndegeneration. Here, following photoreceptor death, microglia assume an early development\u0002like morphology. Finally, we map microglial morphology following optic nerve crush on the \r\nretinal spectrum and observe a layer- and sex-dependent response. \r\nOverall, MorphOMICs opens a new perspective to analyze microglial morphology across \r\nmultiple conditions, and provides a novel tool to characterize microglial morphology beyond \r\nthe traditionally dichotomized view of microglia.","lang":"eng"}],"tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","short":"CC BY (4.0)"},"has_accepted_license":"1","file":[{"date_updated":"2023-04-12T22:30:03Z","creator":"cchlebak","file_size":23890382,"date_created":"2023-01-25T14:31:32Z","embargo_to":"open_access","file_id":"12379","access_level":"closed","content_type":"application/vnd.openxmlformats-officedocument.wordprocessingml.document","file_name":"Gloria_Colombo_Thesis.docx","checksum":"8cd3ddfe9b53381dcf086023d8d8893a","relation":"source_file"},{"content_type":"application/pdf","access_level":"open_access","file_name":"Gloria_Colombo_Thesis.pdf","checksum":"8af4319c18b516e8758e9a6cb02b103b","relation":"main_file","embargo":"2023-04-11","creator":"cchlebak","date_updated":"2023-04-12T22:30:03Z","file_size":13802421,"date_created":"2023-01-25T14:31:36Z","file_id":"12380"}],"department":[{"_id":"GradSch"},{"_id":"SaSi"}],"month":"11","supervisor":[{"orcid":"0000-0001-8635-0877","first_name":"Sandra","last_name":"Siegert","id":"36ACD32E-F248-11E8-B48F-1D18A9856A87","full_name":"Siegert, Sandra"}],"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","citation":{"mla":"Colombo, Gloria. <i>MorphOMICs, a Tool for Mapping Microglial Morphology, Reveals Brain Region- and Sex-Dependent Phenotypes</i>. Institute of Science and Technology Austria, 2022, doi:<a href=\"https://doi.org/10.15479/at:ista:12378\">10.15479/at:ista:12378</a>.","apa":"Colombo, G. (2022). <i>MorphOMICs, a tool for mapping microglial morphology, reveals brain region- and sex-dependent phenotypes</i>. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/at:ista:12378\">https://doi.org/10.15479/at:ista:12378</a>","ista":"Colombo G. 2022. MorphOMICs, a tool for mapping microglial morphology, reveals brain region- and sex-dependent phenotypes. Institute of Science and Technology Austria.","chicago":"Colombo, Gloria. “MorphOMICs, a Tool for Mapping Microglial Morphology, Reveals Brain Region- and Sex-Dependent Phenotypes.” Institute of Science and Technology Austria, 2022. <a href=\"https://doi.org/10.15479/at:ista:12378\">https://doi.org/10.15479/at:ista:12378</a>.","short":"G. Colombo, MorphOMICs, a Tool for Mapping Microglial Morphology, Reveals Brain Region- and Sex-Dependent Phenotypes, Institute of Science and Technology Austria, 2022.","ieee":"G. Colombo, “MorphOMICs, a tool for mapping microglial morphology, reveals brain region- and sex-dependent phenotypes,” Institute of Science and Technology Austria, 2022.","ama":"Colombo G. MorphOMICs, a tool for mapping microglial morphology, reveals brain region- and sex-dependent phenotypes. 2022. doi:<a href=\"https://doi.org/10.15479/at:ista:12378\">10.15479/at:ista:12378</a>"},"language":[{"iso":"eng"}],"oa":1}]