The impact of proliferating mast cells in the developing brain

增殖的肥大细胞对发育中的大脑的影响

基本信息

批准号：
10463954
负责人：
Alexa Ciesinski Blanchard
金额：
$ 3.99万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-11 至 2026-04-10
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10463954
关键词：
Address Adolescent Adult Affect Affective Age B-Lymphocytes Behavior Bioinformatics Bone Marrow Brain Cell Count Cell Maintenance Cell Shape Cells Child Childhood Choroid Chronic Clinical Communication Complex Data Development Developmental Process Diagnosis Disease Embryo Fissural Fostering Foundations Functional disorder Growth Factor Health Helper-Inducer T-Lymphocyte Heterogeneity Hippocampus (Brain)Histamine Homeostasis Immersion Immune Immunologist Inflammatory Innate Immune System Invaded Life Mediator of activation protein Mentorship Microglia Molecular Morphology Neuraxis Neurodegenerative Disorders Neurodevelopmental Disorder Neuroglia Neuroimmune Neurologic Neurologist Neurons Pathology Pattern Pediatric Neurology Perinatal Peripheral Phenotype Physicians Physiological Physiological Processes Population Positioning Attribute Process Proliferating Rattus Reflex action Regulation Research Role Schizophrenia Scientist Shapes Signal Transduction Site Skin Source Specificity Stimulus Supporting Cell Techniques Testing Thalamic structure Time Tissues Training Tumor-infiltrating immune cells Vascular Endothelial Growth Factors autism spectrum disorder blood-brain barrier permeabilization brain cell brain tissue career cell injury cognitive function cytokine experimental study granulocyte hippocampal fissure immunogenic injured insight lateral ventricle mast cell mastocytosis neonatal brain nervous system disorder neurodevelopment neurogenesis neuron development novel perinatal period postnatal recruit relating to nervous system release factor response single-cell RNA sequencing stem synaptogenesis trafficking transcriptome transcriptomics

项目摘要

Project Summary Both resident and peripheral immune cells are increasingly implicated in the pathophysiology of various neurodevelopmental disorders, including autism, but the mechanisms by which these non-neuronal cells impact the brain is largely unknown. Infiltrating immune cells in the brain readily respond to environmental triggers, promoting persistent proinflammatory signaling that permanently alters developing cells and damages non- renewing populations. The resident immune cells of the brain, microglia, regulate normal physiologic processes to guide brain development, but little is known about the contribution of infiltrating immune cells to these same processes. In my preliminary studies, I found thousands of mast cells, a component of the innate immune system, inhabiting the lateral ventricles adjacent the hippocampus, throughout perinatal stages of brain development. This raises the question – what role might such proinflammatory cells serve in the developing brain? Mast cells (MC) are both highly sensitive to a variety of stimuli and reflexively produce a wide assortment of vasoactive molecules, cytokines, and growth factors, making them a potential neuro-immune hub during neurodevelopment. Moreover, since mast cells are so exquisitely responsive to inflammatory signals, they may serve dual functions: potentially supporting cell genesis and maturation, or perpetrating damage. This proposal seeks to address gaps in our understanding of MC recruitment, heterogeneity, and function in the developing brain to assess how this population may contribute to neurodevelopmental disorders. We have shown, for the first time, that brain MC are replicating along the hippocampal fissure and are maintained in this region for the first two postnatal weeks, paralleling neurogenesis and microglial maturation occurring nearby. Advanced flow cytometric techniques will test the hypothesis that they are locally proliferating, which MC do not typically do outside of the bone marrow (Aim 1.1). To elucidate their functional and molecular identity in the developing CNS, we will perform single cell RNA-sequencing of brain MCs and compare their transcriptome to prototypical MCs from the skin and bone marrow (Aim 1.2). Findings from transcriptomic analyses will guide exploration of their mechanism of influence on typical developmental processes in the hippocampus. Lastly, MC are well known to coordinate with microglia in the injured adult brain, but this relationship has not been thoroughly explored during development. We will test our hypothesis that MCs release signaling factors that promote microglial maturation in the hippocampus (Aim 2). These findings will reframe understanding of the developing brain as an immune-enabled site requiring nuanced neuro-immune interactions to sustain developmental processes. This project fosters training in bioinformatics and immersion in two historically independent fields to prepare me for a career investigating neural-immune communication in health and disease. Scientific mentorship from neuroscientist Dr. Margaret McCarthy and immunologist Dr. Nevil Singh, paralleled by clinical mentorship from neuroimmunologist Dr. David Benavides, will establish a strong foundation for my life as a physician-scientist in the field of child neurology.