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Studying FXS-associated Hypervascularization and BBB Defects Using BBB Assembloids: Unveiling the Underlying Molecular Mechanisms

Award Number: R01MH139612
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/24/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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Studying FXS-associated Hypervascularization and BBB Defects Using BBB Assembloids: Unveiling the Underlying Molecular Mechanisms - Fragile X Syndrome (FXS) is a leading monogenic cause of autism spectrum disorder (ASD), resulting from CGG repeat expansion-mediated silencing of the FMR1 gene and subsequent loss of Fragile X Mental Retardation Protein (FMRP). Recent studies implicate brain vascular and blood-brain barrier (BBB) abnormalities—factors that remain underexplored in ASD/FXS pathogenesis. However, the absence of a human BBB model specific to ASD/FXS has hindered efforts to functionally investigate disease-related cerebrovascular abnormalities and their underlying mechanisms. To address this gap, we have developed BBB assembloid models derived from patient-induced pluripotent stem cells (iPSCs), alongside isogenic and neurotypical controls. Our preliminary findings reveal that FXS BBB assembloids exhibit hypervascularization and BBB breakdown, consistent with postmortem tissue data in ASD/FXS patients. CRISPR-mediated removal of expanded CGG repeats reactivated FMRP expression and rescued these defects, indicating a causal role. Multi-omics analyses further identified dysregulated mTOR and Wnt signaling in FXS BBB assembloids, with FMRP directly binding to mRNAs encoding components of both pathways. Given mTOR’s role in angiogenesis and Wnt’s role in BBB integrity, we hypothesize that FMRP deficiency leads to FXS-associated vascular and BBB pathology through post-transcriptional regulation of the mTOR and Wnt signaling pathways. This study will test our hypothesis through three specific aims: Aim 1: Dissect tissue-specific contributions to FXS-associated hypervascularization and BBB defects using reciprocal assembloids combining neural and vascular components from FXS and isogenic control iPSCs. Single-cell transcriptomics profiling will identify FMRP-regulated gene networks driving these abnormalities. Aim 2: Determine how FMRP loss disrupts mTOR signaling, leading to hypervascularization. CLIP-seq, polysome profiling, and protein analysis will identify mTOR pathway transcripts regulated by FMRP. In addtion, we will assess whether the mTOR inhibitor rapamycin restores normal vasculature in FXS BBB assembloids. Aim 3: Examine how FMRP deficiency disrupts BBB integrity through Wnt signaling inhibition. RNA stability assays, CUT&RUN, and transcriptomics profiling will determine whether FMRP loss destabilizes Wnt pathway transcripts, leading to transcriptional dysregulation of BBB-related genes. Finally, we will test whether pharmacological activation of Wnt signaling can restore BBB function in FXS BBB assembloids This study pioneers the use of genetically defined BBB assembloids to model and dissect human cerebrovascular defects in FXS. By integrating reciprocal assembloids, multi-omics, and functional rescue experiments, we will provide the first mechanistic insights linking FMRP loss to mTOR-driven hypervascularization and Wnt-dependent BBB breakdown. These findings will reshape our understanding of FXS pathophysiology and identify novel therapeutic targets for ASD/FXS-related cerebrovascular dysfunction.


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 = $723,817 )
2026	2026	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Mental Health Research Grants	000	1	8/26/2026	NEW	$723,817
														Subtotal = $723,817

Grand Total All Awards = $723,817

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Studying FXS-associated Hypervascularization and BBB Defects Using BBB Assembloids: Unveiling the Underlying Molecular Mechanisms

Award Number: R01MH139612

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/24/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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