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dc.contributor.advisorFrancis Ka-Ming Chanen_US
dc.contributor.authorPark, Christa
dc.date.accessioned2023-05-03T17:06:17Z
dc.date.available2023-05-03T17:06:17Z
dc.date.issued2023-04-25
dc.identifier.doi10.13028/tyab-cd94en_US
dc.identifier.urihttp://hdl.handle.net/20.500.14038/52023
dc.description.abstractReceptor-interacting serine/threonine protein kinase 1 (RIPK1) is a critical adapter protein with pleiotropic functions that regulate cell survival and death. RIPK1 is essential for immune homeostasis and thus is closely controlled during development and inflammation. RIPK1 overexpression has been implicated in multiple inflammatory disorders such as multiple sclerosis, atherosclerosis, cardiovascular disease, obesity, psoriasis, and tumor growth. To study the effects of the overactivation of RIPK1, a system was established that drives its overexpression in mouse fibroblasts. Remarkably, the overexpression of RIPK1 resulted in the induction of both apoptosis and necroptosis. While apoptosis is known to be immunologically silent, necroptosis is highly inflammatory. Additional assays using chemical inhibitors and genetic knockout mice established that RIPK1 kinase activity promotes both types of cell death. Furthermore, RIPK1-induced apoptosis and necroptosis require caspase 8 and MLKL, respectively, and the absence of both caspase 8 and MLKL inhibits RIPK1-induced cell death. RIPK1 induction activates NF-κB/MAPK and increases cytokine/chemokine production driven by cell death. This system was further explored to elucidate the effects of RIPK1-induced cell death on immune effector cells, revealing that RIPK1-induced apoptosis and necroptosis can promote DC activation. Lastly, to study the role of RIPK1 in DCs and its contribution to intestinal homeostasis and injury, mice lacking RIPK1 in the DC population were characterized. Importantly, RIPK1 functions in DCs to support colon homeostasis, but also plays a detrimental role during DSS-induced colitis. Collectively, these data further provide novel insights into the multifaceted functions of RIPK1 in cell death and inflammation, highlighting its critical contributions to the immune response.en_US
dc.language.isoen_USen_US
dc.publisherUMass Chan Medical Schoolen_US
dc.rightsCopyright © 2023 Christa So-Hyun Parken_US
dc.rights.uriAll Rights Reserveden_US
dc.subjectCell Deathen_US
dc.subjectRIPK1en_US
dc.subjectRIPK3en_US
dc.subjectMLKLen_US
dc.subjectInflammationen_US
dc.subjectIBDen_US
dc.subjectcolitisen_US
dc.subjectcaspase-8en_US
dc.subjectTNFR1en_US
dc.subjectApoptosisen_US
dc.subjectnecroptosisen_US
dc.subjectcolitisen_US
dc.titleThe Molecular Mechanism of RIPK1-Induced Cell Death And Its Impact On The Immune Responseen_US
dc.typeDoctoral Dissertationen_US
atmire.contributor.authoremailchrista.park@umassmed.eduen_US
dc.contributor.departmentPathologyen_US
dc.description.thesisprogramImmunology and Microbiologyen_US
dc.identifier.orcid0000-0001-5003-2199en_US


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