20-αHydroxycholesterol, an oxysterol in human breast milk, reverses mouse neonatal white matter injury through Gli-dependent oligodendrogenesis.
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2023-08
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White matter injuries (WMIs) are the leading cause of neurologic impairment in infants born premature. There are no treatment options available. The most common forms of WMIs in infants occur prior to the onset of normal myelination, making its pathophysiology distinctive, thus requiring a tailored approach to treatment. Neonates present a unique opportunity to repair WMIs due to a transient abundance of neural stem/progenitor cells (NSPCs) present in the germinal matrix with oligodendrogenic potential. We identified an endogenous oxysterol, 20-αHydroxycholesterol (20HC), in human maternal breast milk that induces oligodendrogenesis through a sonic hedgehog (shh), Gli-dependent mechanism. Following WMI in neonatal mice, injection of 20HC induced subventricular zone-derived oligodendrogenesis and improved myelination in the periventricular white matter, resulting in improved motor outcomes. Targeting the oligodendrogenic potential of postnatal NSPCs in neonates with WMIs may be further developed into a novel approach to mitigate this devastating complication of preterm birth.
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Chao, Agnes S, Pavle Matak, Kelly Pegram, James Powers, Collin Hutson, Rebecca Jo, Laura Dubois, J Will Thompson, et al. (2023). 20-αHydroxycholesterol, an oxysterol in human breast milk, reverses mouse neonatal white matter injury through Gli-dependent oligodendrogenesis. Cell stem cell, 30(8). pp. 1054–1071.e8. 10.1016/j.stem.2023.07.010 Retrieved from https://hdl.handle.net/10161/32152.
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Scholars@Duke
Phillip Brian Smith
Dr. Smith completed his residency in pediatrics and a fellowship in neonatal medicine at Duke University Medical Center in 2004 and 2007, respectively. He completed an MHS in clinical research from Duke University in 2006 and an MPH in biostatistics from the University of North Carolina at Chapel Hill in 2009. His research is focused on pediatric drug safety, neonatal pharmacology, and the epidemiology of neonatal infections. Dr. Smith is or has been the protocol chair for more than 14 studies of drugs in infants and children. He is the Principal Investigator for the Environmental Influences on Child Health Outcomes (ECHO) Coordinating Center.
Noelle Elizabeth Younge
Estefany Reyes
Program Start Year: 2017
Shinohara Laboratory
Invasive fungal infections have become a global health challenge, owing to the number of patients with HIV/AIDS and the increase use of immunosuppressive drugs during treatment of cancer and autoimmune patients. C. neoformans (Cn) is a yeast found ubiquitously in the environment that initially causes pulmonary infection as it is inhaled. Cn has a neurotropism to the central nervous system (CNS), but the role of CNS-resident cells remains unknown. My thesis work in the Shinohara Lab focuses on elucidating the role and contributions of (CNS) resident cells during cryptococcal meningoencephalitis. My long-terms goal is to establish an independent research group and continue studying immune mechanisms in infectious diseases, providing valuable insights with the purpose of creating new therapeutics to treat these diseases. I also want to educate and train young scientists, focusing on increasing the presence of underrepresented minorities within the biological sciences.
Mari L. Shinohara
Shinohara Lab Website
Immune responses against pathogens are essential for host protection, but excessive and uncontrolled immune reactions can lead to autoimmunity. How does our immune system keep the balance fine-tuned? This is a central question being asked in my laboratory.
The immune system needs to detect pathogens quickly and effectively. This is performed by the innate immune system, which includes cells such as macrophages and dendritic cells (DCs). Pathogens are recognized by pattern recognition receptors (PRRs) and may be cleared in the innate immune system. However, when pathogens cannot be eliminated by innate immunity, the adaptive immune system participates by exploiting the ability of T cells and B cells. The two immune systems work together not only to clear pathogens effectively but also to avoid collateral damages by our own immune responses.
In my lab, we use mouse models for infectious and autoimmune diseases to understand the cellular and molecular mechanisms of; pathogen recognition by PRRs in macrophages and DCs, initiation of inflammatory responses in the innate immune system, and the impact of innate immune inflammation on the development and regulation of T cell-mediated adaptive immune responses.
Several projects are ongoing in the lab. They are to study (1) the roles of PRR in EAE (an animal model of multiple sclerosis), (2) the interplay between immune cells and CNS (central nervous system)-resident cells during EAE and fungal infection, (3) protective and pathogenic mechanisms of immune cells in the lung during fungal infection and inflammation, and (4) the roles of a protein termed osteopontin (OPN), as both secreted (sOPN) and intracellular (iOPN) isoforms, in regulation of immune responses . Although we are very active in EAE to study autoimmunity, other mouse models, such as graft-versus-host disease (GvHD) is ongoing. Cell types we study are mainly DCs, macrophages, neutrophils, and T cells.
Simon Gray Gregory
Dr. Gregory is the Margaret Harris and David Silverman Distinguished Professor and Director of the Brain Tumor Omics Program in the Duke Department of Neurosurgery, the Vice Chair of Research in the Department of Neurology, and Director of the Molecular Genomics Core at the Duke Molecular Physiology Institute.
As a neurogenomicist, Dr. Gregory applies the experience gained from leading the sequencing of chromosome 1 for the Human Genome Project to elucidating the mechanisms underlying multi-factorial diseases using genetic, genomic, and epigenetic approaches. Dr. Gregory’s primary areas of research involve understanding the molecular processes associated with disease development and progression in brain tumors and Alzheimer’s disease, drug induced white matter injury repair in multiple sclerosis, and the characterization of lesion microenvironmental changes in MS.
He is broadly regarded across Duke as a leader in the development of novel single cell and spatial molecular technologies towards understanding the pathogenic mechanisms of disease development. Dr. Gregory is also the Section Chair of Genomics and Epigenetics at the DMPI and Director of the Duke Center of Autoimmunity and MS in the Department of Neurology.
Ronald Norman Goldberg
1. Perinatal asphyxia and neuroprotection - use of umbilical cord blood transfusion
2. Persistent Pulmonary hypertension - use of ethyl nitrite
3. The extremely low-birth-weight infant.
4. Newborn screening - use of digital microfluidics
Eric James Benner
As a neonatologist, my research interests revolve around improving the survival and quality of life of high-risk neonates cared for in Neonatal Intensive Care Units. My primary interest is perinatal brain injuries impacting both full-term infants and those born prematurely. One of the most common forms of perinatal brain injury involves damage to white matter (myelin). My laboratory has developed models of perinatal brain injury to investigate how the endogenous neural stem cell responds to myelin injury. Our hope is to develop innovative strategies to successfully redirect stem cells into the oligodendrocyte lineage and promote myelination after injury. In order to successfully restore myelination after injury, we want to better understand the molecular mechanisms governing 2 important aspects of myelin development.
First, we must understand the molecular signals that drive neural stem cells to differentiate into oligodendrocytes (oligodendrogenesis) and how brain injury impacts this process. This interest has led my laboratory to investigate intracellular and extracellular changes that occur in the neural stem cell niche following injuries that lead to white matter damage.
Secondly, after stem cell commitment to the oligodendrocyte lineage has occurred, we must understand the ongoing signals from the neural environment that influence oligodendrocyte maturation. For this work, my laboratory has developed an innovative technology to remotely control ion channels non-invasively using magnetic fields. Using this technology, we are developing strategies to alter the activity of targeted neural circuits both in utero as well as postnatally to understand the impact of altered activity on myelin maturation. Members of my laboratory are also currently using this technology to understand how altered temperature-gated channel activity in utero may contribute to birth defects associated with maternal fevers.
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