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Mitochondrial uncoupling protein 2 (UCP2) prevents neuronal death in stressed hippocampal neurons

Award Number: R21NS100508
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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The goal of this project is to test the hypothesis that the mitochondrial uncoupling protein UCP2 expressed in neurons and astrocytes can provide effective protection for neurons of the hippocampus in a model of seizure-induced cell death. Uncoupling proteins are powerful controllers of metabolism and the production of reactive oxygen species in the mitochondria. In previous work we demonstrated that UCP2 could protect mouse and primate neurons from a variety of excitotoxic and oxidative insults. Most relevant is our previous finding that overexpression of UCP2 in all cells gave significant protection to hippocampal neurons in the pilocarpine-induced seizure model proposed here. UCP2 also decreases neuronal cell death in various other CNS regions and protects them from the excitotoxic effects of glutamate agonists. We recently showed that the ability of the cytokine LIF to protect astrocytes from peroxide induced death was dependent on a STAT3-mediated induction of UCP2 RNA. Astrocytes are known to respond to oxidative stress, such as that seen in seizure-induced hyperactivity, by several changes including decreased ability to take up glutamate and to release cytotoxic cytokines such as TNFalpha. Our hypothesis is that increasing UCP2 will decrease reactive oxygen species and prevent these astrocyte responses. In Aim 1 we will test the hypothesis that conditional knockout and conditional overexpression of UCP2 in eother neurons or astrocytes will increase and decrease respectively the amount of cell death in the pyramidal cells of the hippocampus. We will use a tamoxifen-activated Cre-recombinase expressed under the control of eother a GFAP or a Thy-1 promoter. When crossed with mice containing a floxed UCP2 gene or a transgene cassette including a floxed segment that prevents expression, these mice will allow the selective deletion or overexpression of UCP2. After tamoxifen treatment, these mice, and untreated littermate controls, will be subjected to pilocarpine-induced seizures and 24 hr later the extent of cell death in the hippocampus measured. The natural expression of UCP2 is controlled at both the transcriptional and translational levels. We have previously shown that neuroprotective factors can increase the levels of UCP2 RNA but not protein. Oxidative stress rapidly increases translation of this RNA to increase UCP2 protein. In Aim 2 we will explore this further and test the hypothesis that the translational regulation is mediated by specific microRNAs. We will first identify the spectrum of candidate regulatory microRNAs by identifying those that alter expression following pilocarpine-induced seizures in ways that correlate with changes in UCP2 expression. We will test the effect of increasing or decreasing the level of a specific microRNAs on UCP2 expression. Together these studies will provide insights into the mechanism of action of a key regulator of oxidative stress and point to ways of exploiting this molecule as a valuable therapeutic target.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2022 ( Subtotal = -$442 )
2022	2019	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	11/21/2021	NON-COMPETING CONTINUATION	-$442
														Subtotal = -$442

Issue Date FY: 2019 ( Subtotal = $191,625 )
2019	2019	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY DR C1607	HERSHEY	PA	17033	DAUPHIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/7/2019	NON-COMPETING CONTINUATION	$191,625
														Subtotal = $191,625

Issue Date FY: 2018 ( Subtotal = $229,950 )
2018	2018	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY DR C1607	HERSHEY	PA	17033	DAUPHIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/11/2018	NEW	$229,950
														Subtotal = $229,950

Grand Total All Awards = $421,133

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Mitochondrial uncoupling protein 2 (UCP2) prevents neuronal death in stressed hippocampal neurons

Award Number: R21NS100508

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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