The Arnold lab is interested in the communication between blood vessel and brain progenitor cells (radial glia) during brain development, and how this communication is altered in pediatric brain diseases, including congenital hydrocephalus, germinal matrix hemorrhage and cerebral palsy. To this end, our lab uses a combination of transcriptomic analysis and mouse genetics to discover novel roles for endothelial cells in brain and blood brain barrier development. We are particularly interested in the role of two factors that appear to “couple” brain progenitor cell growth and differentiation with vascular development. 1) We discovered that the integrin aVb8 on radial glia promotes both endothelial and microglia maturation by activating a “feed forward” TGFb circuit. Mice and humans with genetic deficits in this signaling pathway develop spontaneous brain hemorrhage, hydrocephalus and microglia activation, resulting in downstream neuromotor symptoms highly similar to humans with germinal matrix hemorrhage, congenital hydrocephalus and cerebral palsy. 2)We developed a mouse model for a genetic form of congenital hydrocephalus called proliferative vasculopathy and hydranencephaly-hydrocephalus (PVHH) or Fowler Syndrome (OMIM 225790), and discovered that the heme transporter, Flvcr2, regulates endothelial heme and vascular sprouting in the brain. Our lab continues to investigate the role of integrins, TGFb, and unique transporters such as Flvcr2 in brain vascular development and human brain diseases.
Betsy Crouch is working on the vasculature in the CNS. The vasculature is increasingly recognized to impact brain function in health and disease, including depression, neurodegeneration, neuroinflammation, and neurogenesis. As another example of neurovascular crosstalk, 20% of extremely preterm babies experience hemorrhage specifically in an area of the brain called the ganglionic eminences (GE). The GE are located directly next to the ventricle in the developing brain and are filled with abundant radial glia, which function as neural stem cells. Based on studies in mice, it is postulated that the majority of cortical interneurons are born in the GE. Hemorrhage in this area can therefore cause permanent brain damage and death, and no treatments exist. Most studies of brain vasculature to date use adult mouse models and there are critical gaps to our understanding of how the vasculature interacts with the developing nervous system. Very little is known about human brain vasculature at all. We are studying human brain vascular development using postmortem human tissue, Fluorescence Activated Cell Sorting (FACS), single-cell RNA sequencing and brain organoid models. The goal of these experiments is to delineate the stages of human vascular development and conceptualize treatments for hemorrhage in preterm infants and other human brain pathologies.
The Fancy lab studies oligodendrocytes in the CNS. Oligodendrocytes are the myelinating cells of the CNS that enable formation of myelin and saltatory nerve conduction. Disorders of oligodendrocytes and white matter are associated with human newborn neurological injuries leading to Cerebral palsy (CP). Damaged myelin sheaths and oligodendrocytes (OL) can be regenerated in these conditions by oligodendrocyte precursor cells (OPCs) in a process called remyelination. But myelin repair often fails, contributing significantly to ongoing neurological dysfunction and disease progression, and can fail because of failed OPC migration/recruitment into lesions or from their failed differentiation into mature OL. We have recently shown that OPCs migrate around the CNS using blood vessels as the physical scaffold for their motility, identifying critical oligodendroglial-vascular interactions that determine OPC dispersal during development and disease. Images show OPCs migrating on blood vessels in both normal human brain development and in the newborn neurological injury Hypoxic Ischemic Encephalopathy, as well as an electron micrograph of human myelin sheaths.
The Ferriero Lab utilizes advanced imaging techniques combined with molecular probing in animal models of stroke and hypoxia-ischemia. We have shown that hypoxic-ischemic injury results in prolonged and delayed cell death both locally and in remote regions after the insult and that oxidative stress is critically important in determining cell death. We are currently focusing our efforts on understanding the role of the transcription factor, hypoxiainducible factor 1 alpha in neonatal ischemia. Targeted deletion worsens damage after ischemia and pups with the deletion cannot be preconditioned, suggesting an important role in neuroprotection. Utilizing C13 hyperpolarized MRS, we are attempting to identify which animals will need therapy after the insult as evidenced by excess lactate/pyruvate, and using this information, we will study downstream pathways like HIF and cold inducible RNAs for their involvement in the continued evolution of injury. These data have important consequences for future studies because they suggest that there is prolonged window of opportunity for the administration of neuroprotective agents.
Dr. Dawn Gano is a fetal and neonatal neurologist with a clinical research program focused on studying brain injury, brain development and long-term neurodevelopmental outcomes in critically ill newborns with a foundational goal of helping all children thrive. She has a particular interest in understanding the causes and consequences of cerebellar injury in the preterm population, and collaborates closely with colleagues from neuroradiology, engineering, child psychiatry and psychology to study this prevalent form of preterm brain injury. She is also currently evaluating the feasibility of using robotic exoskeleton technology as a mobility aid and mode of habilitation in children with cerebral palsy.
Dr. Hannah Glass is a Professor of Neurology, Pediatrics, and Epidemiology & Biostatistics at the University of California, San Francisco. She is a neonatal neurologist, the Program Director of the Neonatal Neurology Fellowship, and Director of Neonatal Critical Care Services at the UCSF Benioff Children's Hospital. The goal of Dr. Glass’ research program understand risk factors for adverse outcome following early brain injury, and to develop effective strategies for optimizing outcomes in this high-risk population. Dr. Glass is a Principal Investigator of the Neonatal Seizure Registry, a 9-site collaborative that has received >$7M in funding to examine seizures in the developing brain. She has received funding from NIH (NINDS & NICHD), March of Dimes, Cerebral Palsy Alliance, the Pediatric Epilepsy Research Foundation, and the Patient Centered Outcomes Research Institute.
Orit Glenn serves as Director of Pediatric Neuroradiology and Co-Director of the Advanced Fetal Imaging Program at UCSF. Dr. Glenn's research goals include the development and application of advanced MRI techniques in order to understand normal brain development and to improve the detection of developmental brain disorders, improve our understanding of the etiology and pathogenesis of developmental brain disorders; and to translate this knowledge into improved prenatal counseling and future studies on the prevention and treatment of developmental brain disorders. Her research efforts to date have contributed to our understanding of normal fetal brain development, fetal ventriculomegaly, callosal dysgenesis, and other developmental brain disorders.
NEUROREPAIR - The developing brain is distinct from the mature brain in vulnerability and plasticity. Vulnerability refers to cell injury patterns that occur via different mechanisms over a prolonged period of time, while plasticity refers to the ability of the immature brain to activate endogenous responses to initiate long-term repair. The Gonzalez lab is focused on taking advantage of cell-type specific injury and repair mechanisms in the newborn brain, and defining therapeutic strategies to enhance long-term function and neurodevelopment. These include specific neuronal subpopulations, and their interaction with the developing and injured vasculature, that are critical in the response to both injury and delayed treatment strategies to enhance repair.
A critical goal of translational research is taking findings from in vivoand in vitrobasic science models and determining pathways to safely study these findings in human patients who are at risk for early brain injury. Our projects focused on efficacy of exogenous treatment with the growth factor erythropoietin demonstrated not only altered cell fate and increased neurogenesis following early injury, but also long-term cognitive improvement in small animal models. This treatment protocol, in combination with therapeutic hypothermia, is now being studied in the Phase III HEAL trial in human newborns. We continue to investigate different delayed treatment strategies to enhance long-term repair focused on the neurovascular unit, using stem cells, growth factors, and small molecule agonists of specific pathways. Robust modeling and examination will determine the most effective long-term strategies to maximize outcomes in newborns at risk for early brain injury.
Early life is a critical time in immune development marked by rapid exposure to environmental antigens. Microbial colonization of mucosal tissues plays a key role in the development and education of the host immune system and influences the susceptibility to immune-mediated diseases. Infants born preterm are predisposed to prenatal immune activation and inflammation leading to complications such as periventricular leukomalacia (PVL), the leading cause of cerebral palsy in preterm infants. In utero infection is the most frequently identified cause of spontaneous preterm birth and fetal T cell activation is an independent predictor of severe neonatal morbidity, yet how alterations in microbial colonization predispose premature infants to inflammatory complications such as PVL is not known. Joanna Halkias' teams work has identified a novel effector T cell population in the healthy fetal intestine which associates with the presence of viable bacteria. Bacterial strains isolated from fetal meconium exhibited species-specific capacity to modulate the behavior of intestinal T cells, suggesting that host-microbe interactions influence human immune development in utero. We utilize transcriptomics, functional characterization, and humanized mouse models to understand the cellular and molecular interactions that instruct immune cells during this critical window of development. We hypothesize that identifying patterns of immune dysregulation in early life is fundamental to elucidating mechanisms of disease pathogenesis in perinatal inflammatory pathologies
Hypoxic-ischemic encephalopathy remains a significant cause of death and disability in infants and children. Xiangning Jiang's research efforts are centered on understanding the molecular mechanisms of oxidative injury and the excitotoxic signaling mediated by the NMDA glutamate receptors in the developing brain. In particular, we investigate the role of postsynaptic density (PSD) proteins, including the family of membrane-associated guanylate kinases and the Src family kinases, in regulating NMDA receptor function and the related signaling networks in neonatal brain hypoxia-ischemia (HI). We recently expanded our work to study brain cholesterol metabolism in the immature brain and how it is modified after HI and contributes to brain injury or long-term functional repair.
Luke Judge's group aims to cure genetic diseases using state-of-the-art genome-engineering technology. We leverage two key technological advances to achieve this goal: 1. CRISPR gene editing enzymes and 2. Patient-derived induced pluripotent stem cell (iPSCs). We use patient iPSCs to derive engineered tissues carrying disease mutations that could benefit from therapeutic genome editing with CRISPR. We focus on modeling diseases in iPS cells, then developing and testing the effect of genome editing strategies. We are currently focused on severe autosomal dominant neuropathy and cardiomyopathy. These proof-of-concept studies are aimed at rare mutations with the highest chance of a measurable clinical impact.
Dr. Yi Li has received a Research Scholar Grant from the Radiological Society of North America to study MRI predictors of short-term clinical outcomes in neonates with acute symptomatic seizures. Dr. Li works with Dr. Hannah Glass and the neurologists in the Neonatal Seizure Registry on this research. The results will lay the foundation for studies of early intervention based on imaging findings, and have a positive impact on patients, families, and providers.
Synapse formation is an essential aspect of brain development and is disrupted in neurodevelopmental disorders including autism, epilepsy, and schizophenia. Healthy brain development depends on the dynamic interactions of multiple cell types, including neurons, astrocytes, and microglia. It is increasingly clear that immune signaling also impacts the brain, not only in pathology, but during development and homeostasis. Anna Molofsky's group has identified new roles for cytokine signaling in modulating microglial function, synaptic development, and extracellular matrix remodeling. In ongoing projects, we continue to use transcriptomics, mouse genetics, and imaging to study neuroimmunity and neuron-glial communication in development, plasticity and behavior.
The Nowakowski lab studies the developmental processes that give rise to the cerebral cortex. We utilize a wide range of genomic technologies to probe and perturb critical developmental mechanisms, including signaling pathways and genes, and study their function in neuronal and glial differentiation and maturation. We hypothesize that genomic, transcriptomic, morphological and physiological characterization of cell types in the human brain over the course of development will be critically required to predict consequences of neurodevelopment and neuropsychiatric gene mutations, and to develop therapeutic strategies.
The Ostrem Lab uses animal models, observational clinical research and interventional (clinical trial) approaches. Areas of interest include hypoxic ischemic encephalopathy and neurological problems of prematurity, such as white matter injury. These disorders can have livelong consequences, including developmental delays, disability, and seizures. We are also interested in understanding how maternal health and exposures impact fetal brain development. The Ostrem Lab collaborates with many other labs and investigators to identify, validate, and test potential treatments and to further our understanding of the basic biology of neonatal brain disorders.
The Paredes lab studies cortical development to understand the molecular and cellular basis of neuropsychiatric conditions, such as epilepsy, and brain malformations, Our hypothesis is that the gyrencephalic brain has evolved developmental processes and a prolonged timeline that, when disrupted, will lead to cortical disorganization and aberrant connectivity. We are currently focused on identifying features of neuronal progenitor proliferation and migration, with an emphasis on the perinatal period, that are unique to the gyrated brain. Our approach is to advance ways to directly investigate the human brain and to better model its development using gyrencephalic systems like the piglet cortex.
The nervous system has a limited capacity for regeneration. Why stem cells abundant in the brain are unable to restore damaged tissue has remained a mystery. The Petersen Lab utilizes stem cell and animal models of neurological disease and translational studies of human tissue and blood biomarkers to define the molecular mechanisms that inhibit nervous system repair. Our group discovered critical links between blood coagulation, inflammation, and stem cell dysfunction at sites of vascular damage in the injured brain. We are designing therapies that target toxic blood proteins and inflammatory signals at the blood-brain interface to overcome the inhibitory environment and promote regeneration and normal brain development after neonatal brain injury.
During development, cells and molecules of the central nervous system (CNS) execute an astonishingly intricate choreographed process that culminates in the precise localization of neurons wired in functional networked circuitry. In the PiaoLab, we seek to understand aspects of this process whose perturbation may persist into adulthood and manifest as neurodevelopmental conditions including autism, schizophrenia and cerebral palsy. Specifically, we study how glial cells interact with neurons and extracellular matrix (ECM) during development and how errors in those communications lead to neurological diseases. Our group has uncovered how individual members of the adhesion G protein-coupled receptor (aGPCR) family interact with multiple binding partners in cell-type-specific fashion, making them indispensable for tissue architecture and circuit wiring in the brain as well as developmental myelination of peripheral nerves. In ongoing projects, we continue to use transcriptomics, proteomics, mouse genetics, and imaging to study glial-glial and neuron-glial communications in development and diseases.
Research in the Pleasure lab focuses on two different areas – 1) Understanding the role of morphogenic signals in cortical development and postnatal hippocampal neurogenesis. Most recently in this area are studies of Sonic Hedgehog signaling in the control of developmental and adult neurogenesis. This work also examines the role of morphogenic signals in the regulation of neurogenesis after seizures. This work relies on the use of engineered mouse mutants, neuroanatomical techniques, stereotactic injections of viruses for cellular manipulation, transcriptomics and embryo manipulation using electroporation. 2) Characterizing and understanding the pathophysiology of autoantibody associated neuroinflammatory diseases. This focus of the lab studies the developmental pathophysiology of anti-NMDAR encephalitis using developmental mouse models and is also examining the mechanisms of autoantibody induced injury during embryonic life in mice. In addition, the lab also has an important role in the identification of novel autoantibody associated neurologic disorders that are frequently paraneoplastic or post-infectious.
Newborn babies with complex congenital heart disease (CHD) are now surviving into adulthood with advances in surgical and peri-operative care. Many of these children face neurodevelopmental difficulties as they grow older. Using advanced quantitative magnetic resonance imaging, our team has shown that brain development is delayed early in life and that neonatal brain injury, such as white matter injury is common among newborn babies with complex CHD. Our research group is focused on understanding and improving development and quality of life in these children in order for them to thrive. The Heart & Brain Research Program aims to 1) Understand the causes of delayed brain development in congenital heart disease; 2) Identify fetal predictors of neonatal brain injury and neurodevelopmental outcomes and 3) Identify possible neuroprotective interventions, beginning in fetal life, after birth, around surgery and into childhood. Our research program studies brain development in utero and continues to follow these babies after birth, through infancy and later in life, where we hope to repeat brain imaging to identify complete structural and functional brain circuitry that can be correlated with detailed neuropsychological assessment of brain function. This longitudinal assessment allows our research team to fully understand factors across the lifespan that can influence neurodevelopmental outcome and quality of life.
The Vexler Lab examines the underlying mechanisms of perinatal stroke, focusing on the interplay between neuroinflammation and peripheral inflammation via the blood-brain barrier (BBB) and at the blood-CSF-brain interface (the choroid plexus, CP). We are using a unique model of perinatal arterial stroke in various reporter mice in conjunction with an array of methodologies, such as in vivo MRI and bioluminescence imaging, biochemical assays, transcriptome, CRISPR and RiboTag approaches. Some of our discoveries include demonstration that: 1) the BBB is more integrant after neonatal stroke compared to that after adult stroke; 2) leukocyte trafficking via the CP modulates stroke injury; 3) the main immune cells of the brain—microglial cells—protect neonatal brain after acute stroke; 4) extracellular vesicles (microvesicles and exosomes) released from microglial cells after neonatal stroke modulate injury; 5) mesenchymal stem cells (MSC) enhance brain repair after neonatal stroke in part via released microvesicles and exosomes; and 6) Omega-3 enriched diet during gestation and lactation markedly changes brain lipid composition and protects from perinatal stroke. Currently we focus on how extracellular vesicles alter cell-cell interactions in injured neonatal brain and on whether sphingosine-1-phospate receptor (S1PR1/2) signaling mediates neuroprotection by Omega-3 enriched diet. The figure demonstrates communication of microglial-derived microvesicles (P3-MEV) derived from injured neonatal brain with activated Iba1+ microglial cells.
Yvonne Wu is a child neurologist and epidemiologist, whose research focuses on finding new ways to prevent and treat neurologic injury in full term newborn infants. As a clinical researcher, she specializes in helping to transform important discoveries made at the bench into new clinical treatments available at the bedside. Currently she is the PI of the High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial. This NIH-funded phase 3 randomized controlled trial involves 500 newborn infants born at 21 hospitals across the country and will determine whether high doses of erythropoietin given to newborns during the first week of age is an effective neuroprotective therapy for hypoxic-ischemic encephalopathy.