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Protein Arginine Methyltransferase-Mediated Vascular Dementia in Sickle Cell Disease

Award Number: R01NS132291
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: 04/15/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Protein Arginine Methyltransferase-Mediated Vascular Dementia in Sickle Cell Disease - Project Summary Sickle cell disease is one of the most common recessive inherited blood disorders in African Americans affecting 70,000-100,000 individuals in the U.S. Sickle cell disease is caused by mutations in the β-globin (p- globin) gene, which leads to hemoglobin abnormalities. Sickle cell disease patients chronically suffer from oxygen deprivation due to depressed oxygen-carrying capacity of hemoglobin S causing transient ischemic attacks, and multiple organ dysfunction. Hypoperfusion following vaso-occlusion leads to insufficient blood supply to the brain resulting in anaerobic metabolism, thus activating the inflammatory response. It is not surprising that sickle cell disease -related vascular dementia may be prevalent. Sickle cell disease can decrease memory and cognitive function including shortened attention spans, spatial function, and reading. These pathologies are thought to be caused by the vascular obstructions caused by the sickle cell disease brain. Vascular insufficiency can lead to loss of cerebral blood flow autoregulation and impaired cognitive function related to chronic brain hypoxia. Altogether, these neurological sequelae of sickle cell disease mirrors vascular dementia and similarities of Alzheimer's disease and related dementias (ADRD). Due to these similarities, we compared the etiologies of sickle cell disease and ADRD, and examined the common mechanism(s) of these inter-related events in vascular dementia. We originally discovered that protein arginine methyltransferases (PRMT4) is enhanced in aged 3xTg- AD mice v. younger counterparts, this makes the age-dependent PRMT4 a novel and relevant target against ADRD. More importantly, PRMT4 is increased in female Townes mice, a model of sickle cell disease, leading to subsequent investigations of PRMT4 in sickle cell disease. To our knowledge, this is the first time that PRMT4 has been identified in sickle cell disease (Townes mice). It is also well-known that sickle cell disease can trigger vaso-occlusive crisis that can exacerbate brain hypoperfusion and disturb cerebral blood flow. We seek to identify PRMT4-mediated neuroinflammatory markers to prevent blood brain barrier breakdown in the Townes brain. Therefore, our central hypothesis is inhibition of PRMT4 (TP-064 or PRMT4-AAV) can enhance nitric oxide signaling, neurovascular coupling, and preserve functional learning/memory in aged Townes female mice. We describe PRMT4 inhibition as a therapeutic potential against sickle cell disease-related vascular dementia.


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: 2026 ( Subtotal = $729,635 )
2026	2026	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	4/2/2026	EXTENSION WITH OR WITHOUT FUNDS	$729,635
														Subtotal = $729,635

Grand Total All Awards = $729,635

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Protein Arginine Methyltransferase-Mediated Vascular Dementia in Sickle Cell Disease

Award Number: R01NS132291

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: 04/15/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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