R01NS123168

Defective Heme Transport in the Development of Congenital Hydrocephalus - 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. However, there are critical gaps in our knowledge of disease etiology due to the lack of informative models.

We have developed a mouse model for proliferative vasculopathy and hydranencephaly hydrocephalus (PVHH), a genetic form of CH caused by a 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. Preliminary studies have also shown that neural cells produce and export large amounts of heme, NPC strongly express the heme exporter FLVCR1A, and NPC-specific deletion of FLVCR1A causes a hydrocephalus phenotype similar to FLVCR2 mutant mice. 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:

Aim 1: 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.

Aim 2: 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.

Aim 3: 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 an associated increase in the HIF target gene, VEGF. Hypoxia and increased VEGF are 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.

San Francisco Regents Of The University Of California

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

San Francisco, California 941432324 United States

Single Zip Code

Disease Mechanisms of Prenatal and Pediatric Hydrocephalus (R01 Clinical Trial Not Allowed) (PA-18-622)

Amendment Since initial award the total obligations have increased 368% from $666,598 to $3,120,419.