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Minocycline as a potential therapy for neuroinflammation and cognitive deficit in sickle cell disease

Award Number: R01HL156024
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/15/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Minocycline as a potential therapy for neuroinflammation and cognitive deficit in sickle cell disease - Project Abstract Cognitive and behavioral (anxiety and depression) deficits are two potentially life-altering complications of sickle cell disease (SCD). Loss of full-scale intelligence quotient (IQ), interference with employability, navigation of healthcare resources and overall quality of life are some of the consequences of cognitive deficit in SCD patients. The molecular and cellular factors that mediate the development of these complications are still largely unknown. This proposal aims to define the role of neuroinflammation in development of abnormal neuroplasticity and how the two are temporally related to onset of cognitive and behavioral deficit in SCD. We will also attempt to identify some small molecules and treatment strategies that could have utility in prevention and/or treatment of SCD- associated cognitive and behavioral deficit. Our preliminary studies have shown that sickle cell mice developed cognitive and behavioral deficit that occur with age and neuroinflammation and thus our central hypothesis is that the development of cognitive deficits in SCD is due to neuroinflammation and abnormal neuroplasticity defined by decreased density of dendritic arbors, dendritic spines and, the proportion of immature dendritic spines. We will also examine the potential role or contribution from cerebral infarcts and microvasculopathy. This will be rigorously tested with the following aims (1) Determine the temporal relationship between presence of cognitive (learning and memory) deficit in SCD, and abnormal neuroplasticity and/or the burden of cerebral infarcts and microvasculopathy. This will enable us to establish a temporal relationship between the onset of cognitive and behavioral deficit, and onset of abnormal neuroplasticity as well as the burden of cerebral microinfarct. (2) Demonstrate the role of neuroinflammation, as well as the therapeutic benefit of minocycline in treating cognitive deficits in SCD. This will be done by establishing baseline relationship between onset and progression of cellular and molecular evidence of neuroinflammation and onset and progression of abnormal neuroplasticity as well as development of cognitive and behavioral deficit. Additionally, we will examine whether blocking neuroinflammation could be a potential target for the treatment or prevention of SCD associated cognitive and behavioral deficit. (3) Determine whether treatment with a neurotrophin agonist treatment or anti-neuroinflammatory mediators reverses neuroinflammation, abnormal neuroplasticity and cognitive deficit in SCD. These studies are design to enable us identify small molecule(s) and/or small molecule target(s) and provide the preclinical information that could support a clinical trial geared towards identifying treatment and prevention strategies for cognitive and behavioral deficit in SCD.


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: 2025 ( Subtotal = $774,957 )
2025	2025	CINCINNATI UNIV OF	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cardiovascular Diseases Research	001	6	11/14/2024	SUPPLEMENT FOR EXPANSION	$235,090
2025	2025	CINCINNATI UNIV OF	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Blood Diseases and Resources Research	000	6	11/12/2024	NON-COMPETING CONTINUATION	$539,867
														Subtotal = $774,957

Issue Date FY: 2024 ( Subtotal = $826,471 )
2024	2024	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Blood Diseases and Resources Research	001	5	12/7/2023	SUPPLEMENT FOR EXPANSION	$235,090
2024	2024	CINCINNATI UNIV OF	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Blood Diseases and Resources Research	002	5	6/26/2024	NON-COMPETING CONTINUATION	$48,276
2024	2024	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Blood Diseases and Resources Research	000	5	11/30/2023	NON-COMPETING CONTINUATION	$543,105
														Subtotal = $826,471

Issue Date FY: 2023 ( Subtotal = $845,304 )
2023	2023	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Blood Diseases and Resources Research	002	4	2/11/2023	NON-COMPETING CONTINUATION	$61,021
2023	2023	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Blood Diseases and Resources Research	000	4	12/1/2022	NON-COMPETING CONTINUATION	$549,193
2023	2023	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Blood Diseases and Resources Research	001	4	12/6/2022	SUPPLEMENT FOR EXPANSION	$235,090
														Subtotal = $845,304

Issue Date FY: 2022 ( Subtotal = $631,946 )
2022	2022	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Blood Diseases and Resources Research	000	3	11/19/2021	NON-COMPETING CONTINUATION	$568,751
2022	2022	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Blood Diseases and Resources Research	002	3	6/15/2022	NON-COMPETING CONTINUATION	$63,195
2022	2021	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Blood Diseases and Resources Research	001	1	4/14/2022	NEW	$0
														Subtotal = $631,946

Issue Date FY: 2021 ( Subtotal = $613,980 )
2021	2021	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Blood Diseases and Resources Research	001	1	3/5/2021	NEW	$61,397
2021	2021	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Blood Diseases and Resources Research	000	1	12/15/2020	NEW	$552,583
2021	2021	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Blood Diseases and Resources Research	002	1	6/23/2021	NEW	-$286,061
2021	2021	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Blood Diseases and Resources Research	003	2	6/25/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$286,061
														Subtotal = $613,980

Grand Total All Awards = $3,692,658

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Minocycline as a potential therapy for neuroinflammation and cognitive deficit in sickle cell disease

Award Number: R01HL156024

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/15/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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