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Understanding the contribution of BCL11A to neuron function and neurological disease

Award Number: R01NS146992
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: 02/01/2026
PERIOD OF PERFORMANCE END DATE: 01/31/2031

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Understanding the contribution of BCL11A to neuron function and neurological disease - PROJECT SUMMARY BCL11A is a zinc-finger transcription factor that has been well-studied in erythroid biology, but evidence for an important role in the brain is beginning to emerge. Patients with heterozygous loss-of-function BCL11A mutations present with clinical features that can include intellectual disability (ID), autism spectrum disorder (ASD), and epilepsy. BCL11A is identified as a high confidence ASD risk gene in the SFARI database, and multiple lines of evidence also support potential roles in the etiology of schizophrenia (SZ) and Alzheimer’s disease (AD). However, the mechanisms that link BCL11A to these clinically challenging disorders are poorly understood. To better understand the neuronal function of BCL11A, we performed a series of preliminary behavioral analyses following the selective heterozygous deletion of Bcl11a from excitatory and/or inhibitory neurons in the mouse brain. Surprisingly, we found that Bcl11a deletion from inhibitory GABAergic interneurons (GINs) resulted in social deficits, hyperactivity, and increased seizure susceptibility. Furthermore, we observed increasing levels of BCL11A expression and physical occupation at predicted binding motifs during differentiation and maturation of GINs derived from human induced pluripotent stem cells (iPSCs). Additionally, we found that GIN-enriched ventral forebrain organoids derived from BCL11A-null iPSCs display differential gene expression signatures that overlap with pathological changes in the prefrontal cortex of postmortem brains of individuals with ASD and SZ. Taking these observations together, we hypothesize that the clinically challenging neurological phenotypes associated with BCL11A mutations likely reflect the specific impact of altered BCL11A function on different classes of neurons, with GINs being particularly vulnerable. We will test this hypothesis through a comprehensive series of in vitro (Aim 1) and in vivo (Aim 2) approaches. In Aim 1, we will identify and compare the gene targets of BCL11A in human iPSC-derived excitatory neurons and GINs. We will also employ single-nucleus (sn)RNA-seq and snATAC-seq along with whole-cell patch clamp electrophysiology and histology to establish the overlapping and distinct roles of BCL11A in human neuron populations. In Aim 2, we will further explore the in vivo function of Bcl11a by determining the behavioral and physiological effects of deleting Bcl11a in a neuron type-specific manner in mice. We will also use a chemogenetic approach to further interrogate GIN subtype-specific contributions to BCL11A disease mechanisms. Our long-term goal is to translate these findings into a better understanding of the role of BCL11A in the brain, which will help guide treatment development for patients with BCL11A dysfunction and other GIN-associated disorders.


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 = $575,485 )
2026	2026	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/27/2026	NEW	$575,485
														Subtotal = $575,485

Grand Total All Awards = $575,485

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Understanding the contribution of BCL11A to neuron function and neurological disease

Award Number: R01NS146992

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: 02/01/2026

PERIOD OF PERFORMANCE END DATE: 01/31/2031

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