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PROTECTIVE ROLE OF NEUREGULIN-1 AGAINST CEREBRAL MALARIA PATHOGENESIS AND MORTALITY

Award Number: R01NS091616
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2016
PERIOD OF PERFORMANCE END DATE: 03/31/2021

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PROTECTIVE ROLE OF NEUREGULIN-1 AGAINST CEREBRAL MALARIA PATHOGENESIS AND MORTALITY - ¿ DESCRIPTION (provided by applicant): Severe malaria kills about 900,000 children a year and impairs brain function in some survivors. Human CM (HCM) is a severe form of malaria characterized by sequestration of parasitized red blood cells (pRBCs) in cerebral micro-circulation and induction of inflammatory mediators which cause impaired consciousness with unarousable coma. We reported [PLoS One, 2012;7(3):e34280)] that excess production of heme, a by-product of Plasmodium berghei-damaged erythrocytes during infection, is a major cause of inflammation, loss of blood brain barrier (BBB) integrity and tissue damage associated with fatal experimental cerebral malaria (ECM) . Excess free heme induces up-regulation of STAT3 and CXCL10 whereas up-regulation of HO-1, an essential enzyme in heme catabolism, limits sequestration of pRBC, induction of inflammatory mediators and brain tissue damage caused by ECM. Following a screen for agents that attenuate ECM, we identified Neuregulin- 1(NRG-1), a 8 kDa peptide currently undergoing clinical trials for use against traumatic brain injury, that attenuates mortality, limits sequestration of pRBC, induces anti-inflammatory mediators and reduces brain tissue damage in ECM when delivered intravenously or intra-peritoneally at 5µg/kg (J Neuro,2014:11:9). NRG- 1 mediated attenuation of mortality was via perturbation of expression of a network of pro-inflammatory and anti-inflammatory factors during ECM pathogenesis. We observed that ECM resistant mice (BALB/c) constitutively expressed higher levels of NRG-1 in brain tissue than ECM susceptible (C57BL/6) mice. In human malaria, serum NRG-1 was higher in mild malaria cases but lowest in fatal HCM indicating a possible inhibitory role of infection on endogenous serum NRG-1 production. Expression of NRG-1 in brain tissue, on the other hand, was dependent on expression of ErbB4, a NRG-1 receptor, in damaged brain regions. Since NRG-1 negatively regulates STAT3 and CXCL10 (a key biological determinant of fatal ECM) and positively regulates HO-1, our goal is to functionally assess the key pathways perturbed by NRG-1 to attenuate ECM and HCM pathogenesis. Our main hypothesis is that NRG-1 attenuates CM mortality by down regulating CXCL10 and STAT3 activation and up regulating HO-1. The proposed study focuses on the mechanism by which NRG- 1 regulates the heme-STAT3-CXCL10-HO-1 system to protect against fatal ECM. Three specific aims are proposed. Specific Aim 1: will test the hypothesis that NRG-1 is essential for protection of brain microvascular endothelium and blood-brain barrier (BBB) against heme-induced damage in human CM pathogenesis. Specific Aim 2: will test the hypothesis that NRG-1 is essential for protection against ECM-induced CNS damage and neurobehavioral outcomes via heme-STAT3-CXCL10-HO-1 signaling pathway. Specific Aim 3: will test the hypothesis that NRG-1 attenuates severe HCM by restoring integrity of human blood-brain barrier. Understanding the protective effect of NRG-1 against CM pathogenesis and mortality will provide opportunities for discovery of a new class of small molecule adjunctive therapeutics and interventions against fatal CM.


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 = -$9,794 )
2022	2019	MOREHOUSE SCHOOL OF MEDICINE, INC.	720 WESTVIEW DR SW	ATLANTA	GA	30310	FULTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	10/24/2021	NON-COMPETING CONTINUATION	-$9,794
														Subtotal = -$9,794

Issue Date FY: 2019 ( Subtotal = $310,625 )
2019	2019	MOREHOUSE SCHOOL OF MEDICINE, INC., THE	720 WESTVIEW DR SW	ATLANTA	GA	30310	FULTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	3/12/2019	NON-COMPETING CONTINUATION	$310,625
														Subtotal = $310,625

Issue Date FY: 2018 ( Subtotal = $310,625 )
2018	2018	MOREHOUSE SCHOOL OF MEDICINE, INC., THE	720 WESTVIEW DR SW	ATLANTA	GA	30310	FULTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	3/1/2018	NON-COMPETING CONTINUATION	$279,562
2018	2018	MOREHOUSE SCHOOL OF MEDICINE, INC., THE	720 WESTVIEW DR SW	ATLANTA	GA	30310	FULTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	4/25/2018	NON-COMPETING CONTINUATION	$31,063
														Subtotal = $310,625

Issue Date FY: 2017 ( Subtotal = $391,845 )
2017	2017	MOREHOUSE SCHOOL OF MEDICINE, INC., THE	720 WESTVIEW DR SW	ATLANTA	GA	30310	FULTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	5/26/2017	NON-COMPETING CONTINUATION	$31,063
2017	2017	MOREHOUSE SCHOOL OF MEDICINE, INC., THE	720 WESTVIEW DR SW	ATLANTA	GA	30310	FULTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	4/21/2017	NON-COMPETING CONTINUATION	$279,562
2017	2016	MOREHOUSE SCHOOL OF MEDICINE, INC., THE	720 WESTVIEW DR SW	ATLANTA	GA	30310	FULTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/17/2017	NEW	$81,220
														Subtotal = $391,845

Issue Date FY: 2016 ( Subtotal = $310,625 )
2016	2016	MOREHOUSE SCHOOL OF MEDICINE	720 WESTVIEW DRIVE, S.W.	ATLANTA	GA	30310	FULTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/11/2016	NEW	$309,531
2016	2016	MOREHOUSE SCHOOL OF MEDICINE	720 WESTVIEW DRIVE, S.W.	ATLANTA	GA	30310	FULTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	4/11/2016	NEW	$1,094
														Subtotal = $310,625

Grand Total All Awards = $1,313,926

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PROTECTIVE ROLE OF NEUREGULIN-1 AGAINST CEREBRAL MALARIA PATHOGENESIS AND MORTALITY

Award Number: R01NS091616

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2016

PERIOD OF PERFORMANCE END DATE: 03/31/2021

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