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Defective heme transport in the development of congenital hydrocephalus

先天性脑积水发生过程中血红素运输缺陷

基本信息

批准号：
10280666
负责人：
Thomas Darmody Arnold
金额：
$ 66.66万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10280666
关键词：
Affect Biological Assay Birth Blood Vessel Tissue Blood Vessels Brain Cell Differentiation process Cell Proliferation Cells Cerebrospinal Fluid Clinical Complex Congenital Hydrocephalus DNA Sequence Alteration Data Development Disease Endothelial Cells Endothelium Environmental Risk Factor Etiology Gene Deletion Genes Genetic Genetic Transcription Goals Growth Heme Hemeproteins Human Human Genetics Hydranencephaly Hydrocephalus Hypoxia Hypoxia Inducible Factor Immunohistochemistry In Vitro Knowledge Link LoxP-flanked allele Measures Metabolism Modeling Movement Mus Mutant Strains Mice Mutation Neurologic Neurons Nutrient Online Mendelian Inheritance In Man Oxygen Pathogenesis Pathology Pathway interactions Pharmacological Treatment Pharmacology Phenotype Process Proteins Proteomics Reporter Research Role Secondary to Signal Transduction Source Syndrome Techniques Testing Tissues Up-Regulation Vascular Diseases Vascular Endothelial Cell Vascular Endothelial Growth Factors Vascular Endothelium Vascularization Work angiogenesis base bevacizumab brain abnormalities brain endothelial cell conditional knockout genetic approach heme 1 heme a in vivo information model innovation mouse model nerve stem cell notch protein oxygen transport trafficking

项目摘要

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 aims will explore a new role for heme in the development of PVHH, with the broader goal of understanding and identifying new treatment targets for other forms of CH.

项目总结/文摘