Sunday, May 11, 2025 5/11/2025

The role of metabolic and hemodynamic reserve in age-related brain vulnerability in pediatric sickle cell anemia

Award Number: R01NS121065
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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The role of metabolic and hemodynamic reserve in age-related brain vulnerability in pediatric sickle cell anemia - PROJECT ABSTRACT If oxygen supply to the brain does not match its demands, cellular functions are impeded and can lead to cell death. A margin is created between oxygen supply and brain demand by metabolic and hemodynamic reserves. Our preliminary data show that children may have less reserve due to the critical, but costly energy demands of brain growth and maturation. We have shown that lower oxygen supply (hypoxemia) also decreases reserves, and during childhood, may result in impaired brain growth and development. Children with sickle cell anemia (SCA) have chronic hypoxemia due to reduced hemoglobin. Children with SCA have smaller brain volumes and decreased cortical thickness than unaffected children. The intersection of hypoxemia and brain development is poorly understood, impeding our ability to optimize brain development and neurologic outcomes in children with hypoxemia. The goal of this project is to identify physiologic mechanisms of vulnerability and age-dependent consequences of hypoxemia. Our central hypothesis is that the high cerebral metabolic demand in younger children decreases oxygen reserve, resulting in an age-dependent increased risk for impaired brain growth in children with lower oxygen supply. First, we will assess normal developmental changes in metabolic and hemodynamic reserve in 80 healthy children ages 4-21 to determine age-dependence of reserves (Aim 1). Next, we will determine the effects of hypoxemia on metabolic and hemodynamic reserves and the consequence of hypoxemia on brain development. We will compare 40 children with SCA and 40 age and sex-matched controls at baseline and 3 year follow-up imaging, and examine cortical thickness changes in the two cohorts (Aim 2). Finally, we will evaluate whether oxygen reserve increased through hydroxyurea treatment in an SCA cohort impacts long-term brain development. We will utilize a large sickle cell database with 16 years of brain imaging to compare cortical thickness maturation and total brain volumes between treated and untreated children (Aim 3). Determining the age-dependence of hypoxemic vulnerability and its effect on brain development will allow us to personalize treatment strategies for children at high risk for neurodevelopmental injury to be more aggressive during periods of highest vulnerability.


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 = $426,294 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	4/10/2025	NON-COMPETING CONTINUATION	$426,294
														Subtotal = $426,294

Issue Date FY: 2024 ( Subtotal = $496,753 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	2/29/2024	NON-COMPETING CONTINUATION	$460,907
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	5/6/2024	NON-COMPETING CONTINUATION	$35,846
														Subtotal = $496,753

Issue Date FY: 2023 ( Subtotal = $447,649 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	3/10/2023	NON-COMPETING CONTINUATION	$447,649
														Subtotal = $447,649

Issue Date FY: 2022 ( Subtotal = $472,889 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	5/18/2022	NON-COMPETING CONTINUATION	$472,889
2022	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/18/2022	NEW	$0
														Subtotal = $472,889

Issue Date FY: 2021 ( Subtotal = $545,352 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/11/2021	NEW	$545,352
														Subtotal = $545,352

Grand Total All Awards = $2,388,937

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The role of metabolic and hemodynamic reserve in age-related brain vulnerability in pediatric sickle cell anemia

Award Number: R01NS121065

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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