{"id":6374,"date":"2022-09-29T17:16:51","date_gmt":"2022-09-29T21:16:51","guid":{"rendered":"https:\/\/med.virginia.edu\/pathology\/2022\/09\/29\/laryssa-manigat-phd-2021\/"},"modified":"2025-05-16T21:15:34","modified_gmt":"2025-05-17T01:15:34","slug":"laryssa-manigat-phd-2021","status":"publish","type":"post","link":"https:\/\/med.virginia.edu\/pathology\/2022\/09\/29\/laryssa-manigat-phd-2021\/","title":{"rendered":"Laryssa Manigat, PhD, 2021"},"content":{"rendered":"

Diacylglycerol Kinase \u03b1 is a Pharmacologically Targetable Immune Regulator with a Newly Identified Role in Macrophage Activation<\/h1>\n

Advisor:<\/span><\/strong><\/h4>\n

Purow, Benjamin, MD-NEUR Neurology UPG-MD-NEUR Neurology, University of Virginia<\/p>\n

Abstract:<\/span><\/strong><\/h4>\n
\n

The diacylglycerol kinases (DGKs) are a family of lipid kinases whose primary function is the conversion of diacylglycerol (DAG) to phosphatidic acid (PA). There has been mounting evidence indicating that DGK enzymes are implicated in other physiologic processes, ranging from immune cell regulation to cancer progression. DGK\u03b1 in particular is a known promoter of T-cell anergy, and has been demonstrated as a promising therapeutic target in multiple cancers including glioblastoma (GBM) and melanoma. Prior to these following studies, the only significant phenotype observed in DGK\u03b1 knockout (KO) mice has been enhanced T-cell activity. Herein we reveal a novel, macrophage-specific, immune-regulatory function of DGK\u03b1. In bone marrow-derived macrophages (BMDMs) cultured from wild-type (WT) and KO mice, we observed increased responsiveness of KO macrophages to activating stimuli. Knockdown (KD) of Dgka in a murine macrophage cell line resulted in similar increased responsiveness. Demonstrating in vivo relevance, we observed significantly smaller wounds in Dgka-\/- mice with full-thickness cutaneous burns, a complex wound healing process in which macrophages play a key role. The burned area also had increased numbers of macrophages. In a cortical stab wound model, Dgka-\/- brains show increased Iba1+ cell numbers at the needle track versus that in WT brains.
\nTargeting DGK\u03b1 in order to stimulate T-cell function or to combat its tumorigenic effects in cancer is feasible due to the existence of several small-molecule inhibitors. R59949 and R59022 are tool compounds which limit the DGK\u03b1 conversion of DAG to PA. The compound ritanserin was originally implicated clinically as a serotonin receptor antagonist used for the treatment of schizophrenia and has been used in clinical trial settings with no demonstrated adverse effects. Likely due to ritanserin\u2019s structural similarity to R59949 and R59022, it is also capable of inhibiting DGK\u03b1, with the added benefits of safety and being clinically actionable. In the following studies, we have identified several additional and potentially clinically relevant small molecule compounds from a library of ritanserin analogs which are more potent and specific for DGK\u03b1 than those identified previously. Effective targeting of DGK\u03b1 has promising therapeutic implications, and our newly identified immune regulatory role of DGK\u03b1 is further support for the appeal of developing these compounds. Taken together, these studies present a novel immune-regulatory function of DGK\u03b1 in macrophages with potential implications for wound healing, cancer therapy, and other settings, and the identification of inhibitory compounds to translate these findings therapeutically.<\/p>\n<\/div>\n

Full Dissertation:<\/strong><\/h4>\n

https:\/\/doi.org\/10.18130\/xrqv-yb03<\/a><\/span><\/p>\n","protected":false},"excerpt":{"rendered":"

Diacylglycerol Kinase \u03b1 is a Pharmacologically Targetable Immune Regulator with a Newly Identified Role in Macrophage Activation Advisor: Purow, Benjamin, MD-NEUR Neurology UPG-MD-NEUR Neurology, University of Virginia Abstract: The diacylglycerol kinases (DGKs) are a family of lipid kinases whose primary function is the conversion of diacylglycerol (DAG) to phosphatidic acid (PA). There has been mounting […]<\/p>\n","protected":false},"author":1184,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"inline_featured_image":false,"footnotes":"","_links_to":"","_links_to_target":""},"categories":[41],"tags":[],"class_list":["post-6374","post","type-post","status-publish","format-standard","hentry","category-phd-defenses"],"acf":false,"yoast_head":"\nLaryssa Manigat, PhD, 2021 - Department of Pathology<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/med.virginia.edu\/pathology\/2022\/09\/29\/laryssa-manigat-phd-2021\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Laryssa Manigat, PhD, 2021 - Department of Pathology\" \/>\n<meta property=\"og:description\" content=\"Diacylglycerol Kinase \u03b1 is a Pharmacologically Targetable Immune Regulator with a Newly Identified Role in Macrophage Activation Advisor: Purow, Benjamin, MD-NEUR Neurology UPG-MD-NEUR Neurology, University of Virginia Abstract: The diacylglycerol kinases (DGKs) are a family of lipid kinases whose primary function is the conversion of diacylglycerol (DAG) to phosphatidic acid (PA). 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