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Novel Carbon Nanozyme Mechanisms for Traumatic Brain Injury

Award Number: R01NS094535
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: 09/01/2015
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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Novel Carbon Nanozyme Mechanisms for Traumatic Brain Injury - Abstract: In the prior funding cycle, we successfully obtained a mechanistic understanding of the chemical basis for the excellent therapeutic actions in mild traumatic brain injury (TBI) of our carbon nanoparticle (CNP) platform, poly(ethylene)glycol-hydrophilic carbon clusters (PEG-HCCs). We identified new actions that point to profound new directions for our CNPs. We: 1) discovered that the HCC's broad redox potential extended their action as a redox mediator among mitochondrial constituents involved in electron transport, i.e. a nanoparticle enzyme, or “nanozyme”, and 2) identified a new mechanism by which hemorrhage causes cellular toxicity: rapid and persistent generation of DNA double strand breaks and robust DNA damage response leading to cellular “senescence”, in which cells become a nidus for inflammation. While senescence could be prevented by PEG- HCCs, the cells became sensitized to iron toxicity/ferroptosis. This interaction led us to generate a new CNP, covalently bonding iron chelator, deferoxamine (DEF). Our results indicate DEF-HCC-PEG effectively addressed hemin and iron-related injury, senescence and ferroptosis. Given that mitochondrial dysfunction and hemorrhagic contusion (HC) are associated with poor outcome in TBI, these findings directly indicate the benefit of pursuing these mechanisms. The identification of key mechanistic features of our CNP platform that facilitate a mitochondrial site of action and new mechanism of hemorrhage-induced pathology form the basis for this renewal application. We will incorporate our understanding of the PEG-HCC mechanisms of action to generate a more immediately translatable CNP utilizing a good manufacturing practice (GMP) starting material, activated charcoal, and test them in-vivo in a rodent TBI with hemorrhagic contusion (TBI/HC). Our overall hypothesis is that the mechanisms of action discovered in our prior application will be translatable to GMP starting materials and will act on both the genomic and mitochondrial damage associated with TBI/HC. Specific Aim 1 will test the hypothesis that an oxidizing synthesis environment can be optimized to generate GMP-derived starting materials, PEG-oxidized activated charcoal achieving, the desired characteristics of a CNP nanozyme. Specific Aim 2 will test the hypothesis that DEF-linked CNP will address hemorrhage-related mitochondrial and genomic events triggering senescence and resistance to ferroptosis. Specific Aim 3 will administer the CNPs developed in Aims 1 and 2 to moderate-severe TBI/HC model. Completion of these Aims will yield a more readily translatable version of our CNP platform building on a growing understanding of the critical features and sites of action for their nanozyme mechanisms. New therapeutic targets emerging from a more thorough understanding of pathological mechanisms by which hemorrhage complicates outcome from TBI will guide the design. By employing GMP starting material, this project can generate breakthrough materials more rapidly translatable to the clinic. Because mitochondrial dysfunction and the cellular consequence of hemorrhage are features both of acute injury and of aging and cognitive decline, a broader potential for this therapy is suggested.


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 = $445,251 )
2024	2024	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	4/5/2024	NON-COMPETING CONTINUATION	$445,251
														Subtotal = $445,251

Issue Date FY: 2023 ( Subtotal = $460,990 )
2023	2023	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	5/26/2023	NON-COMPETING CONTINUATION	$460,990
														Subtotal = $460,990

Issue Date FY: 2022 ( Subtotal = $462,899 )
2022	2022	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	3/29/2022	NON-COMPETING CONTINUATION	$462,899
														Subtotal = $462,899

Issue Date FY: 2021 ( Subtotal = $464,753 )
2021	2021	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	6	4/23/2021	NON-COMPETING CONTINUATION	$464,753
2021	2020	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	3/10/2021	COMPETING CONTINUATION	$72,535
2021	2018	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	3/10/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$72,535
														Subtotal = $464,753

Issue Date FY: 2020 ( Subtotal = $504,802 )
2020	2020	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	3/27/2020	COMPETING CONTINUATION	$504,802
2020	2018	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	3/20/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $504,802

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2018	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	4	2/4/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$420,091
2019	2018	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	12/27/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$166,558
2019	2018	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	005	4	2/6/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$166,558
2019	2018	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	4	2/4/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$166,558
2019	2018	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	4	1/22/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$420,091
2019	2017	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/27/2018	NON-COMPETING CONTINUATION	-$166,558
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $420,091 )
2018	2018	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	8/22/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$420,091
2018	2017	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	8/21/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $420,091

Issue Date FY: 2017 ( Subtotal = $424,341 )
2017	2017	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	8/29/2017	NON-COMPETING CONTINUATION	$424,341
														Subtotal = $424,341

Issue Date FY: 2016 ( Subtotal = $424,342 )
2016	2016	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	9/1/2016	NON-COMPETING CONTINUATION	$424,342
														Subtotal = $424,342

Issue Date FY: 2015 ( Subtotal = $454,236 )
2015	2015	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/31/2015	NEW	$454,236
														Subtotal = $454,236

Grand Total All Awards = $4,061,705

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Novel Carbon Nanozyme Mechanisms for Traumatic Brain Injury

Award Number: R01NS094535

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: 09/01/2015

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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