The molecular mechanisms that promote neuronal death and thus neurological dysfunction after stroke (focal cerebral ischemia) are not understood completely. We and others showed that focal ischemia leads to extensive temporally orchestrated changes in the mRNA expression in rodents. Due to their position between the genomic DNA and functional proteins, mRNAs are considered as the key controllers of the cellular functions. However, recent studies showed that several small, non-coding, evolutionarily conserved RNAs known as microRNAs (miRNAs) control mRNA levels and function in various organisms including vertebrates. No studies to date examined whether the cerebral miRNA profiles will be altered in the post-ischemic brain and if yes, those changes have any functional significance in promoting the brain damage. This R21 proposal wishes to analyze the following hypotheses. (1) Focal ischemia alters cerebral miRNA profiles that might contribute in part to the post-ischemic pathological events and thus brain injury, (2) Endogenous and exogenous neuroprotective strategies act in part by modulating the miRNA profiles in the post-ischemic brain and (3) preventing the function of specific miRNAs that are upregulated in the post-ischemic brain using miRNA inhibitors can affect the down-stream targets and the stroke outcome. The long-term goal is to understand the role of miRNA in ischemic brain damage and to develop novel molecular therapies to modulate miRNAs.

Public Health Relevance

Stroke is the 3rd leading cause of death in adult population all over the world. Currently very few options are available for designing effective treatment paradigms to prevent stroke-induced neurological dysfunction. Understanding the molecular mechanisms that mediate the pathological events like inflammation, edema and ionic imbalance which ultimately promote neuronal death after stroke is important to develop novel therapies. While tens of thousands of messenger RNAs (mRNAs) control the formation of various proteins and thus cellular functions, few hundreds of small microRNAs control mRNA levels in cells. To date no studies evaluated the significance of miRNAs in stroke-induced brain damage. The goals of this proposal is to analyze if stroke alters miRNA profiles in rodent brain and if yes, whether those changes respond to pharmacological and endogenous neuroprotective paradigms. We will also analyze if miRNA levels and function can be modulated in brain to change the functional outcome of stroke in future.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS061071-02
Application #
7560016
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Bosetti, Francesca
Project Start
2008-03-01
Project End
2012-02-29
Budget Start
2009-03-01
Budget End
2012-02-29
Support Year
2
Fiscal Year
2009
Total Cost
$160,781
Indirect Cost
Name
University of Wisconsin Madison
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Mehta, Suresh L; Vemuganti, Raghu (2018) Ischemic Stroke Alters the Expression of the Transcribed Ultraconserved Regions of the Genome in Rat Brain. Stroke 49:1024-1028
Vemuganti, Raghu; Zhao, Heng (2015) Mechanisms and therapies for acute CNS insults. Metab Brain Dis 30:353
Mehta, Suresh L; Dharap, Ashutosh; Vemuganti, Raghu (2014) Expression of transcribed ultraconserved regions of genome in rat cerebral cortex. Neurochem Int 77:86-93
Vemuganti, Raghu (2013) All's well that transcribes well: non-coding RNAs and post-stroke brain damage. Neurochem Int 63:438-49
Dharap, Ashutosh; Pokrzywa, Courtney; Murali, Shruthi et al. (2013) MicroRNA miR-324-3p induces promoter-mediated expression of RelA gene. PLoS One 8:e79467
Dharap, Ashutosh; Nakka, Venkata Prasuja; Vemuganti, Raghu (2012) Effect of focal ischemia on long noncoding RNAs. Stroke 43:2800-2
Dharap, Ashutosh; Nakka, Venkata Prasuja; Vemuganti, Raghu (2011) Altered expression of PIWI RNA in the rat brain after transient focal ischemia. Stroke 42:1105-9
Dharap, Ashutosh; Vemuganti, Raghu (2010) Ischemic pre-conditioning alters cerebral microRNAs that are upstream to neuroprotective signaling pathways. J Neurochem 113:1685-91
Vemuganti, Raghu (2010) The MicroRNAs and Stroke: No Need to be Coded to be Counted. Transl Stroke Res 1:158-160
Dharap, Ashuthosh; Bowen, Kellie; Place, Robert et al. (2009) Transient focal ischemia induces extensive temporal changes in rat cerebral microRNAome. J Cereb Blood Flow Metab 29:675-87