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NITRIC OXIDE PROTECTS AGAINST MICROCIRCULATORY COMPLICATIONS OF MALARIA

Award Number: R01HL087290
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2009
PERIOD OF PERFORMANCE END DATE: 12/31/2011

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NITRIC OXIDE PROTECTS AGAINST MICROCIRCULATORY COMPLICATIONS OF MALARIA - We propose that low nitric oxide (NO) bioavailability mediates the microcirculatory complications of severe malaria; NO quenching by cell-free hemoglobin (Hb) released as an unavoidable consequence of parasite replication and low NO production due to hypoargininemia lead to low NO bioavailability. Vascular eak, petechial hemorrhaging, and hypotension are well recognized complications of experimental cerebral malaria (ECM), and the proposed studies will determine whether poor tissue oxygenation also functions in malaria pathogenesis by altering blood flow or functional capillary density. Our observations that (i) free hemoglobin (Hb) is markedly elevated during ECM, (ii) free Hb scavenges nitric oxide (NO) and (iii)marked hypoargininemia occurs during ECM indicate that, in contrast to sepsis, malaria shock is caused by low NO bioavailability. A major controversy in microcirculation research is the role of NO in mediating vascular leak and pathogenesis, and our proposed studies will define its role in vascular leak during ECM. A key prediction of our hypothesis is that exogenous NO should protect against ECM pathogenesis; indeed, NO donor administration significantly (P=0.003) protects animals from the development of disease. The markedly protected NO donor-treated mice abrogated the vascular leak, petechial hemorrhage, hypotension, and impaired NO mediated signaling (cGMP levels) that were detected in saline-injected controls with ECM. These studies will be extended to define whether NO donor administration protects against other microcirculatory dysfunction during ECM, such as low tissue perfusion and oxygenation (aim 1). Adhesion of parasitized erythrocytes (pRBCs), platelets, and leukocytes occur during ECM and deficiency of selected cell adhesion molecules protects against malaria pathogenesis. We will inter relate the results of the microcirculatory complications of ECM to cell adhesion and eCAM expression to define the cellular and molecular mechanisms whereby cell adhesion contributes to disruption of the blood brain barrier and pathogenesis and identify whether and how exogenous NO protects against ECM cell adhesion (aim 2). The final aim will assess by bioassay (arteriolar dilation, and venular leak) and actual measurement (NO electrode) whether NO bioavailability is impaired during ECM and restored by the protective NO donor. The response of eNOS to ECM and NO donor treatment will also be elucidated; a detailed understanding of in vivo eNOS responses to free Hb or to low NO bioavailability that occurs during other diseases (sickle cell anemia) is currently lacking. Besides providing new information about the microcirculation, the proposed studies may lead to adjunct therapy for malaria that rescues millions of children from death or impaired cognition. These studies will also address long standing controversies about malaria pathogenesis, such as whether pRBC adhesion leads to hypoxia and multi-organ failure (sequestration hypothesis).


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: 2011 ( Subtotal = $0 )
2011	2009	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH	LA JOLLA	CA	92037	SAN DIEGO	USA	Trans-NIH Recovery Act Research Support	000	3	8/3/2011	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $0

Issue Date FY: 2010 ( Subtotal = $426,150 )
2010	2010	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH	LA JOLLA	CA	92037	SAN DIEGO	USA	Blood Diseases and Resources Research	000	4	4/13/2010	NON-COMPETING CONTINUATION	$426,150
														Subtotal = $426,150

Issue Date FY: 2009 ( Subtotal = $766,350 )
2009	2009	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH	LA JOLLA	CA	92037	SAN DIEGO	USA	Blood Diseases and Resources Research	000	3	5/14/2009	NON-COMPETING CONTINUATION	$426,150
2009	2009	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH	LA JOLLA	CA	92037	SAN DIEGO	USA	Trans-NIH Recovery Act Research Support	001	3	7/30/2009	SUPPLEMENT FOR EXPANSION	$340,200
														Subtotal = $766,350

Issue Date FY: 2008 ( Subtotal = $426,150 )
2008	2008	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH	LA JOLLA	CA	92037	SAN DIEGO	USA	Blood Diseases and Resources Research	000	2	3/28/2008	NON-COMPETING CONTINUATION	$426,150
														Subtotal = $426,150

Issue Date FY: 2007 ( Subtotal = $426,150 )
2007	2007	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH	LA JOLLA	CA	92037	SAN DIEGO	USA	Blood Diseases and Resources Research	000	1	4/2/2007	NEW	$426,150
														Subtotal = $426,150

Grand Total All Awards = $2,044,800

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NITRIC OXIDE PROTECTS AGAINST MICROCIRCULATORY COMPLICATIONS OF MALARIA

Award Number: R01HL087290

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2009

PERIOD OF PERFORMANCE END DATE: 12/31/2011

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