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Kynurenine metabolites and depression: An in vitro and ex vivo study

Award Number: R21MH107985
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/11/2016
PERIOD OF PERFORMANCE END DATE: 10/31/2019

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Kynurenine metabolites and depression: An in vitro and ex vivo study - DESCRIPTION (provided by applicant): The kynurenine catabolic pathway for tryptophan degradation in humans produces metabolites that are neurologically active and affect neurotransmission and neuronal integrity. Quinolinic acid (QUIN) is a product of the pathway which has been implicated in numerous neuropsychiatric disorders and has been correlated with depression in patients administered the inflammatory cytokine, interferon (IFN)-α. Besides, activation of the kynurenine pathway by inflammation leads to elevated levels of QUIN, which have been shown to cause depressive-like behavior in mice. The mechanism by which QUIN acts in the brain is to activate excitotoxic neurotransmitter pathways involving the amino acid glutamate and by leading to lipid peroxidation. Following metabolism by indoleamine 2,3-dioxygenase and subsequent steps, three consecutive enzymes of the kynurenine pathway determine the metabolic partitioning of tryptophan metabolites to QUIN, picolinic acid (PIC), or further metabolism. We hypothesize that the shift of QUIN and PIC levels is linked to chronic inflammation and major depression. To test this hypothesis, we will, in the first aim, study the structure and action of the enzymes and the mechanisms controlling QUIN and PIC production. In the second aim, a new, rapid and efficient analytical method will be developed for in vitro and ex vivo quantitation of QUIN and PIC levels and will be applied to samples obtained from patient populations expected to exhibit high levels of QUIN as a result of increased inflammation and from assays using purified protein to simulate similar distributions. Through these studies, the correlation between kynurenine metabolites and major depression will be investigated, and small molecule inhibitors will be used as probes for modulating the production of QUIN and PIC levels.


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: 2020 ( Subtotal = -$24 )
2020	2017	UNIVERSITY OF TEXAS AT SAN ANTONIO, THE	1 UTSA CIRCLE	SAN ANTONIO	TX	78249	BEXAR	USA	Mental Health Research Grants	000	2	4/6/2020	NON-COMPETING CONTINUATION	-$24
														Subtotal = -$24

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2017	UNIVERSITY OF TEXAS AT SAN ANTONIO, THE	1 UTSA CIRCLE	SAN ANTONIO	TX	78249	BEXAR	USA	Mental Health Research Grants	000	2	6/25/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $222,688 )
2017	2017	UNIVERSITY OF TEXAS AT SAN ANTONIO	ONE UTSA CIRCLE	SAN ANTONIO	TX	78249	BEXAR	USA	Mental Health Research Grants	001	2	8/15/2017	NON-COMPETING CONTINUATION	$22,270
2017	2017	UNIVERSITY OF TEXAS AT SAN ANTONIO	ONE UTSA CIRCLE	SAN ANTONIO	TX	78249	BEXAR	USA	Mental Health Research Grants	000	2	4/19/2017	NON-COMPETING CONTINUATION	$200,418
														Subtotal = $222,688

Issue Date FY: 2016 ( Subtotal = $197,688 )
2016	2016	UNIVERSITY OF TEXAS AT SAN ANTONIO	1 UTSA CIRCLE	SAN ANTONIO	TX	78249	BEXAR	USA	Mental Health Research Grants	000	1	5/10/2016	NEW	$197,688
														Subtotal = $197,688

Grand Total All Awards = $420,352

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Kynurenine metabolites and depression: An in vitro and ex vivo study

Award Number: R21MH107985

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/11/2016

PERIOD OF PERFORMANCE END DATE: 10/31/2019

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