Stroke is a leading cause of death and disability and the risk for stroke increases with age. The mechanisms that contribute to post-ischemic injury after stroke are not completely understood, and as a result most clinical trials conducted to date for stroke therapeutics have failed. Failure to consider white matter (WM) injury is a critical gap in the development of successful stroke therapy. As mechanisms of WM injury differ from those in gray matter and change with age, an ideal stroke therapeutic must not only be directed towards neuronal and axonal protection across age, but also must restore function when applied after injury. One of our significant research achievements during the previous funding cycle established that Class I HDAC activation contributes to excitotoxicity during ischemia and contributes to oxidative injury during the post-ischemic period by impairing mitochondrial structure and function. Class I HDAC inhibition promotes axon function recovery when applied before or after ischemia in young and aging WM through unknown mechanisms. Our current proposal focuses on the mechanisms of post-ischemic protection conferred by Class I HDAC inhibition in young and aging WM. While little is known about the gene regulatory mechanisms underlying this protective phenomenon, an intriguing reciprocal relationship has emerged between levels of HDACs and miRNAs affecting cellular survival following stroke. Among ischemia-regulated miRNAs, miR-331 is predicted to target Class I HDACs. Ischemia up-regulates Class I HDAC levels in young and aging WM. Our preliminary findings show that ischemia led to decreased levels of miR-331 concomitant with increased HDAC expression and HDAC inhibition upregulated miR-331 above control levels. Consequently, an miR-331 mimic suppresses HDAC levels, indicating a reciprocal regulation between Class I HDACs and miR-331. Furthermore, WM ischemia activates nitric oxide synthase (NOS), leading to oxidative injury via mitochondrial dysfunction, and Class I HDAC inhibition attenuates NOS activity. In light of this information, we propose to further extend these studies by testing our novel hypothesis that Class I HDAC activation mediates WM ischemic injury by contributing to increased oxidative stress, impairing mitochondrial function, and down-regulating glial expression of miR-331. Our overall goal is to determine whether Class I HDACs act directly or recruit NOS or interact with miR-331 to exert post-ischemic injury in young and aging WM. Electrophysiological, biochemical, and mouse genetic in vitro and in vivo approaches will be employed to test the following Specific Aims:
Aim 1 is designed to investigate whether Class I HDAC activation recruits NOS in an age-, cell-, and isoform-specific manner;
Aim 2 is designed to determine whether Class I HDAC activation directly mediates mitochondrial injury during ischemia;
and Aim 3 is designed to establish whether Class I HDACs interact with miR-331 to mediate ischemic WM injury. Overall, the present project will unravel the role of Class I HDAC activity in WM ischemic injury in order to help in the design of novel therapies to minimize post-ischemic injury in patients.

Public Health Relevance

Stroke is a devastating health problem and the risk for stroke increases with age. The impact of this devastating disease will increase enormously as the world population continues to age. The mechanisms that contribute to post-ischemic injury and neurological dysfunction after stroke are not completely understood, and most clinical trials conducted to save neuronal function to date for stroke therapeutics have failed. Failure to consider white matter (WM) injury is a critical gap in the development of successful stroke therapy. An ideal stroke therapeutic must not only be directed towards neuronal and axonal protection across age, but also must restore function when applied after injury. Post-ischemic application of the Class I HDAC inhibitor MS-275 protects neurons, axons, and glial cells and restores function in young and aging brain by preserving mitochondria. Therefore we will determine the mechanisms of post-ischemic protection conferred by Class I HDAC inhibition in young and aging WM. The overall goal of this project is to test if Class I HDAC inhibition can be used to develop novel therapies to help aid recovery after stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
2R01AG033720-07A1
Application #
9308535
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Mackiewicz, Miroslaw
Project Start
2010-09-01
Project End
2022-03-31
Budget Start
2017-04-15
Budget End
2018-03-31
Support Year
7
Fiscal Year
2017
Total Cost
$327,231
Indirect Cost
$122,231
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Bastian, Chinthasagar; Zaleski, Jane; Stahon, Katharine et al. (2018) NOS3 Inhibition Confers Post-Ischemic Protection to Young and Aging White Matter Integrity by Conserving Mitochondrial Dynamics and Miro-2 Levels. J Neurosci 38:6247-6266
Bastian, Chinthasagar; Politano, Stephen; Day, Jerica et al. (2018) Mitochondrial dynamics and preconditioning in white matter. Cond Med 1:64-72
Parpura, Vladimir; Fisher, Elizabeth S; Lechleiter, James D et al. (2017) Glutamate and ATP at the Interface Between Signaling and Metabolism in Astroglia: Examples from Pathology. Neurochem Res 42:19-34
Hu, Xiangyou; Hou, Hailong; Bastian, Chinthasagar et al. (2017) BACE1 regulates the proliferation and cellular functions of Schwann cells. Glia 65:712-726
Saab, Aiman S; Tzvetavona, Iva D; Trevisiol, Andrea et al. (2016) Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism. Neuron 91:119-32
Stahon, Katharine E; Bastian, Chinthasagar; Griffith, Shelby et al. (2016) Age-Related Changes in Axonal and Mitochondrial Ultrastructure and Function in White Matter. J Neurosci 36:9990-10001
Baltan, Selva (2016) Age-specific localization of NMDA receptors on oligodendrocytes dictates axon function recovery after ischemia. Neuropharmacology 110:626-632
Yin, Xinghua; Kidd, Grahame J; Ohno, Nobuhiko et al. (2016) Proteolipid protein-deficient myelin promotes axonal mitochondrial dysfunction via altered metabolic coupling. J Cell Biol 215:531-542
Baltan, Selva (2015) Can lactate serve as an energy substrate for axons in good times and in bad, in sickness and in health? Metab Brain Dis 30:25-30
Baltan, Selva (2014) Excitotoxicity and mitochondrial dysfunction underlie age-dependent ischemic white matter injury. Adv Neurobiol 11:151-70

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