Small ubiquitin-like modifier (SUMO) conjugation modulates all major cellular pathways, including those associated with gene expression and genome stability, protein quality control, proteasomal degradation of proteins and DNA damage repair. Transient cerebral ischemia massively activates SUMO conjugation, resulting in a dramatic rise in levels of SUMO2/3-conjugated proteins. Cell culture studies suggest that the post- ischemic activation of SUMO2/3 conjugation is a protective stress response. However, the role of SUMO conjugation in the fate of post-ischemic neurons in the intact brain and the mechanisms and pathways that link SUMO conjugation to restoration of function impaired by transient ischemia are not known. Without this knowledge it is highly unlikely that the SUMO conjugation pathway can be manipulated for therapeutic purposes. Our long-term goal is to understand how to manipulate the SUMO conjugation pathway for preventive and therapeutic purposes. The objective of this particular application is to elucidate the role of individual SUMO paralogues in the recovery of neurons from ischemic stress and to identify the mechanisms and pathways involved. The central hypothesis is that SUMO conjugation plays a key role in modulating path- ways that are critical for death/survival decisions in post-ischemic neurons. This hypothesis has been formulated on the basis of data produced in our laboratory. The rationale for the proposed studies is that after we have verified the protective role of SUMO conjugation in post-ischemic neurons in vivo and have identified the underlying mechanisms and pathways, we will have established an important platform for designing new strategies for preventive and therapeutic interventions in clinically relevant pathological states associated with a transient episode of insufficient blood supply. Based on strong preliminary data and the development of novel SUMO transgenic and knockout animals in our laboratory, the hypothesis will be tested by pursuing the following specific aims: 1) Characterize new SUMO transgenic and knockout mouse models;2) Determine the effects of individual SUMO paralogues on post-ischemic neuronal cell damage and functional recovery;3) Determine how SUMO conjugation is linked to the fate of post-ischemic neurons;4) Determine how transient ischemia affects the crosstalk between ubiquitin and SUMO conjugation. The approach is innovative because it is the first study to use SUMO transgenic and knockout animals and to per- form proteomic analyses to determine the role of SUMO conjugation in cerebral ischemia. The proposed research is significant, because we expect to uncover the mechanisms that link SUMO conjugation to the viability and function of post-ischemic neurons. Ultimately, such knowledge is expected to translate into new strategies for therapeutic intervention in pathological states associated with an episode of insufficient blood supply and in other disorders associated with the SUMO conjugation pathway, including diabetes, heart failure, and degenerative diseases.

Public Health Relevance

The proposed research is relevant to public health because elucidating the role of small ubiquitin-like modifier conjugation in the life/death decision of pos-ischemic neurons is expected to help identifying new targets for therapeutic intervention. Thus, the proposed research is relevant to the part of NIH's mission to foster fundamental creative discoveries, innovative research strategies, and their applications as a basis to advance significantly the Nation's capacity to protect and improve health.

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National Institute of Neurological Disorders and Stroke (NINDS)
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Neural Oxidative Metabolism and Death Study Section (NOMD)
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Bosetti, Francesca
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Duke University
Schools of Medicine
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Liu, Huaqin; Yu, Zhui; Li, Ying et al. (2018) Novel Modification of Potassium Chloride Induced Cardiac Arrest Model for Aged Mice. Aging Dis 9:31-39
Bernstock, Joshua D; Yang, Wei; Ye, Daniel G et al. (2018) SUMOylation in brain ischemia: Patterns, targets, and translational implications. J Cereb Blood Flow Metab 38:5-16
Jiang, Meng; Yu, Shu; Yu, Zhui et al. (2017) XBP1 (X-Box-Binding Protein-1)-Dependent O-GlcNAcylation Is Neuroprotective in Ischemic Stroke in Young Mice and Its Impairment in Aged Mice Is Rescued by Thiamet-G. Stroke 48:1646-1654
Yu, Zhui; Sheng, Huaxin; Liu, Shuai et al. (2017) Activation of the ATF6 branch of the unfolded protein response in neurons improves stroke outcome. J Cereb Blood Flow Metab 37:1069-1079
Zhang, Lin; Liu, Xiaozhi; Sheng, Huaxin et al. (2017) Neuron-specific SUMO knockdown suppresses global gene expression response and worsens functional outcome after transient forebrain ischemia in mice. Neuroscience 343:190-212
Liu, Shuai; Sheng, Huaxin; Yu, Zhui et al. (2016) O-linked ?-N-acetylglucosamine modification of proteins is activated in post-ischemic brains of young but not aged mice: Implications for impaired functional recovery from ischemic stress. J Cereb Blood Flow Metab 36:393-8
Yang, Wei; Paschen, Wulf (2016) Unfolded protein response in brain ischemia: A timely update. J Cereb Blood Flow Metab 36:2044-2050
Yang, Wei; Sheng, Huaxin; Wang, Haichen (2016) Targeting the SUMO pathway for neuroprotection in brain ischaemia. Stroke Vasc Neurol 1:101-107
Yang, Wei; Paschen, Wulf (2015) SUMO proteomics to decipher the SUMO-modified proteome regulated by various diseases. Proteomics 15:1181-91
Yang, Wei; Sheng, Huaxin; Thompson, J Will et al. (2014) Small ubiquitin-like modifier 3-modified proteome regulated by brain ischemia in novel small ubiquitin-like modifier transgenic mice: putative protective proteins/pathways. Stroke 45:1115-22

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