The focus of this application is on elucidating the molecular mechanisms by which transglutaminase 2 (TG2) regulates hypoxia inducible factor (HIF) signaling and attenuates ischemic-induced cell death. In response to ischemia there is an upregulation of genes that can facilitate either cell survival or cell death. Whether cell survival or delayed cell death is the final outcome is dependent on the complement of ischemia-induced genes expressed, which can differ depending on variables such as duration and severity of the insult and the presence of regulatory proteins. HIF, which is composed of the oxygen sensitive HIF1 subunit and the constitutively expressed HIF12, is the transcription factor that is primarily responsible for the upregulation of hypoxic responsive genes. We have demonstrated that TG2 binds HIF12, attenuates HIF signaling, attenuates the expression of specific HIF- responsive genes and protects against ischemic insult. Furthermore, we have compelling data demonstrating that neuronal expression of human TG2 significantly reduces infarct volume in a mouse stroke model. The central hypothesis of this application is that TG2 is a regulator of hypoxic-induced transcriptional signaling, and that TG2 plays a fundamental role in protecting neurons against ischemia-induced cell death. The objectives of this proposal will be met through three specific aims that test the hypotheses: (1) that the TG2- mediated suppression of HIF signaling is dependent on the localization of TG2 to the nucleus, independent of transamidating activity and requires interaction with HIF12, (2) that the protective effects of TG2 against ischemic-induced cell death are independent of transamidating activity, but require nuclear localization and further, that the interaction of TG2 with HIF1? is necessary for the protective role of TG2 against ischemic insult, and (3) that TG2 attenuates the delayed cell death that occurs in response to stroke in vivo. Overall, this is an integrated, mechanistic and holistic proposal. In our studies we will be using recombinant proteins to define the interacting domains between TG2 and HIF1?, cell models to understand how TG2 modulates HIF dependent transcriptional events and attenuates ischemia-induced cell death, and mouse models to delineate the role of neuronal TG2 in decreasing stroke damage. We believe that by using this full complement of approaches we will be able to more completely understand the role of TG2 in ameliorating ischemia-induced cell death. These are exciting and innovative studies in that they not only define a new framework for understanding the function of TG2, but that they also are providing new insights into the regulation of ischemia-induced cell death processes.

Public Health Relevance

Stroke is a common condition that results in a disturbance in the availability of oxygen in the brain and is of major medical importance as there are approximately 500,000 new ischemic strokes yearly in the USA. In the ischemic brain, cell death occurs very rapidly at the infarct core, however in the surrounding penumbra the cell death is slower and of a more controlled nature and therefore this has been a significant target for interventive therapies. We have recently found that Transglutaminase 2 (TG2) attenuates ischemic-induced cell death in both cell and mouse models and therefore our long range goal is to fully understand the role of TG2 in ameliorating stroke-induced cell death so that effective therapeutics can be developed.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neural Oxidative Metabolism and Death Study Section (NOMD)
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Bosetti, Francesca
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University of Rochester
School of Medicine & Dentistry
United States
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Yunes-Medina, Laura; Paciorkowski, Alex; Nuzbrokh, Yan et al. (2018) Depletion of transglutaminase 2 in neurons alters expression of extracellular matrix and signal transduction genes and compromises cell viability. Mol Cell Neurosci 86:72-80
Quinn, Breandan R; Yunes-Medina, Laura; Johnson, Gail V W (2018) Transglutaminase 2: Friend or foe? The discordant role in neurons and astrocytes. J Neurosci Res 96:1150-1158
Monteagudo, Alina; Feola, Julianne; Natola, Heather et al. (2018) Depletion of astrocytic transglutaminase 2 improves injury outcomes. Mol Cell Neurosci 92:128-136
Feola, Julianne; Barton, Alan; Akbar, Abdullah et al. (2017) Transglutaminase 2 modulation of NF-?B signaling in astrocytes is independent of its ability to mediate astrocytic viability in ischemic injury. Brain Res 1668:1-11
Gundemir, Soner; Monteagudo, Alina; Akbar, Abdullah et al. (2017) The complex role of transglutaminase 2 in glioblastoma proliferation. Neuro Oncol 19:208-218
Monteagudo, Alina; Ji, Changyi; Akbar, Abdullah et al. (2017) Inhibition or ablation of transglutaminase 2 impairs astrocyte migration. Biochem Biophys Res Commun 482:942-947
Yunes-Medina, Laura; Feola, Julianne; Johnson, Gail V W (2017) Subcellular localization patterns of transglutaminase 2 in astrocytes and neurons are differentially altered by hypoxia. Neuroreport 28:1208-1214
Lei, Zhinian; Brizzee, Corey; Johnson, Gail V W (2015) BAG3 facilitates the clearance of endogenous tau in primary neurons. Neurobiol Aging 36:241-8
Eckert, Richard L; Kaartinen, Mari T; Nurminskaya, Maria et al. (2014) Transglutaminase regulation of cell function. Physiol Rev 94:383-417
Gundemir, Soner; Colak, Gozde; Feola, Julianne et al. (2013) Transglutaminase 2 facilitates or ameliorates HIF signaling and ischemic cell death depending on its conformation and localization. Biochim Biophys Acta 1833:1-10

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