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Brain Injury Treatment by Modulation of Hemodynamics with Blood Soluble Drag Reducing Molecules

Award Number: R01NS112808
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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Abstract Traumatic brain injury (TBI) is a major health problem, representing a third of all injury-related deaths in the United States and 70% of long-term disabilities in survivors. Decades of TBI research focused almost exclusively on neuroprotective strategies, has failed to develop any therapeutics for clinical treatment. One less explored potential target is the cerebral circulation. In TBI, there is increasing recognition that the peri-contusional areas of TBI suffer microvascular failure and diffusional hypoxia and edema. Our studies on microvascular shunts (MVS) with high intracranial pressure (ICP) corroborate microcirculatory failure. We propose here modulation of hemodynamics with blood soluble drag reducing polymers (DRP) as a novel treatment modality for TBI that specifically targets cerebral microcirculation and that based on physical but not pharmacological principles. Nanomolar amounts of intravenous DRP reduce blood pressure loss in arterioles by diminishing flow separations and microvortices at vessel bifurcations, increase precapillary pressure and the density of functioning capillaries. Increased vascular wall shear rate may reduce transcapillary macrophage migration and inflammation. We showed that 140 µg/kg of intravenous DRP (ED70) increased blood flow velocity in cerebral arterioles, reduced MVS, restored perfusion in capillaries and reduced tissue hypoxia in a rat model of TBI when i.v. injected 30 minutes after the insult. The next logical step, our objective, is to perform a comprehensive study of the dose and time-related efficacy of DRP and to examine the therapeutic mechanisms involved. Central hypothesis: DRP, through their general dose-dependent action on cerebrovascular microcirculation, can present a unique and effective therapy for TBI, applicable at both, early and later time. The rationale is that unlike other TBI therapies tested thus far, the hemorheological effects of DRP are independent of tissue status in terms of tissue or vascular receptor reactivity or sensitivity for its mechanism of action. Our long-term goal is to optimize the application of DRP after TBI for maximal efficacy on long-term recovery and provide for the first time, a therapeutic intervention that may be effective even if delayed hours after injury. Using the lateral fluid percussion injury TBI model in rats, we will address two aims: 1) to study the acute dose-dependent effects of DRP on the time course and relative changes in cerebral microvascular flow, i.e. MVS, tissue oxygenation and metabolism using in-vivo 2-photon laser microscopy and laser speckle imaging after moderate and severe TBI; and 2) to define the optimal dose and therapeutic time window of DRP for clinically relevant long-term outcomes and mechanisms involved using magnetic resonance imaging, behavioral testing and histology, possible anti-inflammatory effects of rheological modulation will be evaluated by ELISA and immunohistochemistry. To comply with NIH requirement, studies will be done on both sexes to evaluate possible female/male differences. The proposed research is significant since it will provide the first non-pharmacologic rheological treatment for TBI targeting impaired cerebral microcirculation and will reveal the blood flow-related pathogenesis and recovery mechanisms in TBI.


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: 2024 ( Subtotal = -$16,480 )
2024	2023	LOVELACE BIOMEDICAL RESEARCH INSTITUTE	2425 RIDGECREST DR SE	ALBUQUERQUE	NM	87108	BERNALILLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	7	9/26/2024	NON-COMPETING CONTINUATION	-$16,480
2024	2021	LOVELACE BIOMEDICAL AND ENVIRONMENTAL RESEARCH INSTITUTE, INC.	2425 RIDGECREST DR SE	ALBUQUERQUE	NM	87108	BERNALILLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	6/26/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = -$16,480

Issue Date FY: 2023 ( Subtotal = -$45,756 )
2023	2023	LOVELACE BIOMEDICAL RESEARCH INSTITUTE	2425 RIDGECREST DR SE	ALBUQUERQUE	NM	87108	BERNALILLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	7	7/12/2023	NON-COMPETING CONTINUATION	$442,538
2023	2021	LOVELACE BIOMEDICAL RESEARCH INSTITUTE	2425 RIDGECREST DR SE	ALBUQUERQUE	NM	87108	BERNALILLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	5/15/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$197,036
2023	2021	LOVELACE BIOMEDICAL RESEARCH INSTITUTE	2425 RIDGECREST DR SE	ALBUQUERQUE	NM	87108	BERNALILLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/15/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$291,258
														Subtotal = -$45,756

Issue Date FY: 2022 ( Subtotal = $442,538 )
2022	2022	LOVELACE BIOMEDICAL RESEARCH INSTITUTE	2425 RIDGECREST DR SE	ALBUQUERQUE	NM	87108	BERNALILLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	6	9/10/2022	NON-COMPETING CONTINUATION	$442,538
2022	2021	LOVELACE BIOMEDICAL RESEARCH INSTITUTE	2425 RIDGECREST DR SE	ALBUQUERQUE	NM	87108	BERNALILLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	5	8/26/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$1
2022	2021	LOVELACE BIOMEDICAL RESEARCH INSTITUTE	2425 RIDGECREST DR SE	ALBUQUERQUE	NM	87108	BERNALILLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	005	5	9/20/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$291,258
2022	2021	LOVELACE BIOMEDICAL RESEARCH INSTITUTE	2425 RIDGECREST DR SE	ALBUQUERQUE	NM	87108	BERNALILLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	8/17/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$291,259
2022	2021	LOVELACE BIOMEDICAL RESEARCH INSTITUTE	2425 RIDGECREST DR SE	ALBUQUERQUE	NM	87108	BERNALILLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	5	9/15/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$291,258
2022	2021	LOVELACE BIOMEDICAL AND ENVIRONMENTAL RESEARCH INSTITUTE, INC.	2425 RIDGECREST DR SE	ALBUQUERQUE	NM	87108	BERNALILLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	8/26/2022	NON-COMPETING CONTINUATION	-$291,258
														Subtotal = $442,538

Issue Date FY: 2021 ( Subtotal = $449,013 )
2021	2021	LOVELACE BIOMEDICAL AND ENVIRONMENTAL RESEARCH INSTITUTE, INC.	2425 RIDGECREST DR SE	ALBUQUERQUE	NM	87108	BERNALILLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	8/13/2021	NON-COMPETING CONTINUATION	$449,013
														Subtotal = $449,013

Issue Date FY: 2020 ( Subtotal = $449,779 )
2020	2020	LOVELACE BIOMEDICAL & ENVIRONMENTAL RESEARCH INSTITUTE INC	2425 RIDGECREST DR SE	ALBUQUERQUE	NM	87108	BERNALILLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	3	6/9/2020	NON-COMPETING CONTINUATION	$449,779
2020	2019	LOVELACE BIOMEDICAL & ENVIRONMENTAL RESEARCH INSTITUTE INC	2425 RIDGECREST DR SE	ALBUQUERQUE	NM	87108	BERNALILLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	3/9/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$291,062
2020	2019	LOVELACE BIOMEDICAL AND ENVIRONMENTAL RESEARCH INSTITUTE, INC.	2425 RIDGECREST DR SE	ALBUQUERQUE	NM	87108	BERNALILLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	2	5/4/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$16,480
2020	2019	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	1	5/4/2020	NEW	-$16,480
2020	2019	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/9/2020	NEW	-$291,062
														Subtotal = $449,779

Issue Date FY: 2019 ( Subtotal = $334,869 )
2019	2019	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	8/20/2019	NEW	-$1,044
2019	2019	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/17/2019	NEW	$335,913
														Subtotal = $334,869

Grand Total All Awards = $1,613,964

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Brain Injury Treatment by Modulation of Hemodynamics with Blood Soluble Drag Reducing Molecules

Award Number: R01NS112808

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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