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：
10630822
负责人：
Alexa Ciesinski Blanchard
金额：
$ 4.56万
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/10630822
关键词：
Address Adolescent Adult Affect Affective Age Attention B-Lymphocytes Behavior Bioinformatics Bone Marrow Brain Cell Count Cell Maintenance Cell Proliferation Cell Shape Cells Central Nervous System Child Childhood Choroid Chronic Clinical Communication Complex Data Development Developmental Process Diagnosis Disease Embryo Fostering Foundations Functional disorder Growth Factor Health Helper-Inducer T-Lymphocyte Heterogeneity Hippocampus Histamine Homeostasis Immersion Immune Immunologist Inflammation Inflammation Mediators Inflammatory Innate Immune System Invaded Life Mediator Mentorship Microglia Molecular Morphology Neurodegenerative Disorders Neurodevelopmental Disorder Neuroglia Neuroimmune Neurologic Deficit Neurologist Neurons Pathology Pattern Pediatric Neurology Perinatal Peripheral Phenotype Physicians Physiological Physiological Processes Population Positioning Attribute Process Proliferating Rattus Regulation Research Role Schizophrenia Scientist Shapes Signal Transduction Site Skin Source Specificity Stimulus Supporting Cell Techniques Testing Thalamic structure Time Tissues Training Vascular Endothelial Growth Factors autism spectrum disorder blood-brain barrier permeabilization brain cell brain tissue career cognitive function cytokine experimental study glial cell development granulocyte hippocampal fissure immune cell infiltrate immunogenic injured insight lateral ventricle mast cell mastocytosis neonatal brain nervous system disorder neural neurodevelopment neurogenesis neuron development novel perinatal period postnatal recruit 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.

项目概要常驻免疫细胞和外周免疫细胞越来越多地参与各种疾病的病理生理学神经发育障碍，包括自闭症，但这些非神经元细胞影响的机制大脑中的浸润性免疫细胞很容易对环境触发因素做出反应，促进持久的促炎信号传导，永久改变发育中的细胞并损害非大脑中的常驻免疫细胞小胶质细胞负责调节正常的生理过程。指导大脑发育，但人们对浸润免疫细胞对这些发育的贡献知之甚少在我的初步研究中，我发现了数千个肥大细胞，这是先天免疫系统的一个组成部分，在大脑发育的整个围产期，居住在海马体附近的侧脑室。这就提出了一个问题——这些促炎细胞在发育中的大脑中发挥什么作用？ (MC) 对各种刺激高度敏感，并反射性地产生多种血管活性物质分子、细胞因子和生长因子，使它们成为神经发育过程中潜在的神经免疫中心。此外，由于肥大细胞对炎症信号的反应非常灵敏，因此它们可能具有双重功能：可能支持细胞发生和成熟，或造成损害。该提案旨在解决差距。在我们对发育中大脑中 MC 募集、异质性和功能的理解中，以评估这如何我们首次证明，大脑 MC 可能会导致神经发育障碍。沿着海马裂复制并在出生后的前两周内维持在该区域，先进的流式细胞术技术将同时发生附近的神经发生和小胶质细胞成熟。检验它们正在局部增殖的假设，而 MC 通常不会在骨髓外进行增殖（目标 1.1）为了阐明它们在发育中的中枢神经系统中的功能和分子特性，我们将进行单细胞研究。对大脑 MC 进行 RNA 测序，并将其转录组与来自皮肤和骨骼的典型 MC 进行比较骨髓（目标 1.2）。转录组分析的结果将为其影响机制的探索提供指导。最后，众所周知，MC 与小胶质细胞协调。在受伤的成人大脑中，但这种关系在发育过程中尚未得到彻底探索，我们将进行测试。我们的假设是 MC 释放促进海马小胶质细胞成熟的信号因子（目的 2）这些发现将重新构建对发育中大脑作为免疫激活部位的理解。该项目促进了神经免疫相互作用的细微差别以维持发育过程。生物信息学和沉浸在两个历史上独立的领域，为我的职业调查做好准备神经科学家玛格丽特博士对健康和疾病中的神经免疫沟通进行了科学指导。麦卡锡和免疫学家 Nevil Singh 博士，同时还有神经免疫学家 David 博士的临床指导贝纳维德斯博士将为我作为儿童神经病学领域的医师科学家的生活奠定坚实的基础。