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Role of Glia and Inflammation in Altered Synapse Development in Schizophrenia

Award Number: K99MH093458
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/22/2011
PERIOD OF PERFORMANCE END DATE: 02/28/2014

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Role of Glia and Inflammation in Altered Synapse Development in Schizophrenia - DESCRIPTION (provided by applicant): Disturbance in brain development during adolescence may underlie schizophrenia (SZ). Although many reports showed that astrogliosis is not observed in SZ, accumulating evidence suggests that altered function of astrocytes and microglia as well as aberrant immune/inflammatory responses may also underlie SZ. Nonetheless, it is unclear whether or to what extent glial cells and inflammation are involved in altered brain development during adolescence. Recently, we have found that the expression of immune/stress related genes is altered in live neuronal cells derived from SZ patients. The most affected genes include glutathione S-transferase theta 2 (GSTT2) gene, which regulates cellular detoxification system and protects cells from reactive oxygen metabolites. Oxidative stress activates innate immune signaling and contributes to inflammation in various diseases such as diabetes, atherosclerosis, and neurodegenerative disorders. Indeed, we observed increased expression of proinflammatory cytokines by oxidative stress. In the proposed study, we will test the hypothesis that glial cell activation and inflammatory responses during adolescence contribute to altered development of glutamatergic synapses. We will perform in vivo knockdown of GSTT2 expression at specific developmental stages in mice as a model to induce glial cell activation and inflammation via increased oxidative stress. We will characterize the effects of knockdown on the activation of microglia and astrocytes as well as the production of proinflammatory cytokines. We will also assess the effects of knockdown on development of glutamatergic synapses and the expression of synaptic/dendritic immune molecules. Finally, we will address the role of innate immune signaling in microglia by using microglia-specific deletion of MyD88, a molecule that plays a central role in innate immune signaling. The training and research proposal will enable the candidate to develop into an independent investigator in neuropsychiatry research. The project will contribute to the understanding of the roles for glial cells and inflammation in altered brain development during adolescence relevant to SZ.


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: 2014 ( Subtotal = $0 )
2014	2012	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Mental Health Research Career/Scientist Development Awards	000	2	6/10/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2012 ( Subtotal = $72,223 )
2012	2012	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Mental Health Research Career/Scientist Development Awards	000	2	7/12/2012	NON-COMPETING CONTINUATION	$72,223
														Subtotal = $72,223

Issue Date FY: 2011 ( Subtotal = $72,223 )
2011	2011	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Mental Health Research Career/Scientist Development Awards	000	1	8/22/2011	NEW	$72,223
														Subtotal = $72,223

Grand Total All Awards = $144,446

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Role of Glia and Inflammation in Altered Synapse Development in Schizophrenia

Award Number: K99MH093458

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/22/2011

PERIOD OF PERFORMANCE END DATE: 02/28/2014

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