# Defective heme transport in the development of congenital hydrocephalus > **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $619,160 ## Abstract PROJECT SUMMARY/ABSTRACT Congenital hydrocephalus (CH) is a debilitating neurologic condition with complex genetic and environmental inputs, characterized by excessive accumulation of cerebro-spinal fluid (CSF) and enlarged ventricles. Emerging research suggests that disrupted neuroprogenitor cell (NPC) proliferation/differentiation, abnormal brain angiogenesis and hypoxia may be involved in CH pathogenesis. Despite these recent advances there remain critical gaps in our knowledge of disease etiology due to the lack of informative models. We developed a mouse model for Proliferative Vasculopathy and Hydranencephaly Hydrocephalus (PVHH), a genetic form of CH caused by mutation in the heme transporter, Flvcr2. Similar to humans, mice with genetic deletion of Flvcr2 in vascular endothelial cells (ECs) develop abnormal brain blood vessels, tissue hypoxia, disrupted NPC differentiation, and CH. In preliminary studies, we also found that neural cells produce and export large amounts of heme, that NPCs strongly express the heme exporter, Flvcr1a, and that NPC-specific deletion of Flvcr1a causes a hydrocephalus phenotype similar to Flvcr2 mutant mice. Together, this work links abnormal angiogenesis to disrupted brain development and CH, and uncovers a central role for heme in these pathologies. In this proposal, we investigate how heme, a molecule important for carrying oxygen in the body, is involved in the pathogenesis of PVHH. We hypothesize that heme released from NPCs regulates brain angiogenesis and the NPC micro-environment, and that disrupted heme transport causes reduced brain vascularization, tissue hypoxia and downstream hydrocephalus. We will test this hypothesis in three distinct but interrelated aims: In Aim 1, we will determine how heme is trafficked in the brain. Using innovative heme reporters and new proteomics approaches, we will determine the primary cellular source of heme, mechanisms of heme transport/trafficking, and the proteins interacting with heme in the brain. In Aim 2, we will focus on how heme regulates brain angiogenesis in PVHH. Our preliminary data indicate that heme directly regulates Dll4-Notch signaling, a pathway known to suppress angiogenic sprouting and reduce vascular growth. Using pharmacologic treatments and gene perturbations, we will modulate heme and Dll4-Notch signaling in vitro and in vivo, and determine whether Dll4-Notch is sufficient and necessary to produce the PVHH phenotype. In Aim 3, we will determine the specific role of hypoxia and HIF-VEGF signaling in PVHH. In our PVHH models, we observe severe hypoxia, strong upregulation of hypoxic signaling factor HIF2a in NPCs, and associated increase in the HIF target gene, VEGF. Hypoxia and increased VEGF is found in humans with hydrocephalus, and targeting VEGF in mouse models of CH reduces hydrocephalus. Here, we will block HIF-VEGF signaling using genetic and pharmacologic approaches, then determine the impact on the PVHH phenotype. Together, these three ... ## Key facts - **NIH application ID:** 10475201 - **Project number:** 5R01NS123168-02 - **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO - **Principal Investigator:** Thomas Darmody Arnold - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2022 - **Award amount:** $619,160 - **Award type:** 5 - **Project period:** 2021-09-01 → 2026-06-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10475201 ## Citation > US National Institutes of Health, RePORTER application 10475201, Defective heme transport in the development of congenital hydrocephalus (5R01NS123168-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10475201. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*