Efferent vagal modulation of neuropod cells in the small intestine

小肠神经足细胞的传出迷走神经调节

基本信息

批准号：
10683276
负责人：
Melanie Maya Kaelberer
金额：
$ 11.88万
依托单位：
DUKE UNIVERSITY
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：
2022-09-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10683276
关键词：
Address Anatomy Animals Anxiety Area Black race Brain Brain Stem Calcium Cell secretion Cells Cellular Assay Chronic stress Classification Coculture Techniques Communication Complex Data Development Plans Diagnosis Disease Doctor of Medicine Doctor of Philosophy Duodenum Dyspepsia Efferent Neurons Electrophysiology (science)Endocrine Enteroendocrine Cell Epithelial Cells Functional Gastrointestinal Disorders Functional disorder Gastroenterology Gastrointestinal Diseases Genes Glutamates Goals Health Hormones Hypersensitivity Image In Vitro Individual Intestines Irritable Bowel Syndrome Knowledge Link Maps Measures Mentored Research Scientist Development Award Mentors Motivation Nature Nerve Neurobiology Neuroepithelial Neurons Neurotransmitter Receptor Neurotransmitters Nodose Ganglion Norepinephrine Organoids Pathway interactions Patients Persons Public Health Publishing Rabies virus Research Research Personnel Rewards Scaffolding Protein Science Sensory Sensory Physiology Signaling Molecule Simplexvirus Small Intestines Sorting Stimulus Sweetening Agents Symptoms Synapses Testing Time Training United States National Institutes of Health Vagus nerve structure Visceral Work career career development cell motility design detection of nutrient disorders of gut-brain interaction dorsal motor nucleus gastrointestinal gastrointestinal epithelium gut-brain axis in vivo intestinal epithelium millisecond neural circuit neurotransmission neurotransmitter release postsynaptic preference presynaptic rabies viral tracing response sugar targeted treatment vesicular release

项目摘要

ABSTRACT Functional gastrointestinal (GI) diseases are the most common diagnoses in gastroenterology. Such disorders, like irritable bowel syndrome or functional dyspepsia, are recognized by altered GI sensitivity and motility. Though the pathophysiology is complex, a conserved feature is the bidirectional alteration in brain- gut signaling. Thus, these are classified as disorders of brain-gut interaction. While the vagus nerve is the main brain-gut link, how the brain relays neural signals that modulate GI epithelial sensory function is unknown. My long-term career goal is to document how neural circuits originating from the brain alter the gut’s ability to sense nutrients. With the support of the NIH Mentored Research Scientist Development Award — K01, the objective of this proposal is to delineate a brain-to-gut neural circuit that could be used to alter sensory transduction at the gut epithelium. This will be accomplished in three aims: Aim 1. Determine the neurotransmitters and hormones released by intestinal sensory cells in response to excitatory neurotransmitter stimulation. An in vitro organoid and sorted single cell assay will be used to measure release in culture. This aim will demonstrate that an excitatory neurotransmitter can stimulate vesicular release in enteroendocrine cells. Aim 2. Pair vagal stimulation with sensory epithelial cell calcium imaging and electrophysiology to evaluate the functional connectivity of vagal neurons synapsing onto intestinal sensory cells. This aim will demonstrate a functional connection where neurons increase the excitability of sensory cells in the proximal small intestine. Aim 3. Utilize both retrograde (post- to pre-synapse) rabies virus and anterograde (pre- to post- synapse) herpes simplex virus to trace a mono-synaptic connection between the brainstem and intestinal sensory epithelial cells. This aim will establish an anatomical map for how the brainstem is connected to neuropod cells. Identifying functional neural circuits connecting the brain and the gut will enable the understanding of the mechanisms behind visceral hypersensitivity. Together with my mentoring team, we have designed this project to provide me with the necessary research and professional training for me to excel as an independent investigator in the field of sensory neurogastroenterology.

抽象的功能性胃肠道（GI）疾病是胃肠病学中最常见的诊断。这样的肠易激综合征或功能性衰退等疾病被GI敏感性改变和运动。尽管病理生理学很复杂，但保守的特征是大脑的双向改变肠道信号传导。这是将这些归类为脑肠相互作用的疾病。而迷走神经是主脑脉络链接，大脑如何传递调节胃肠道上皮感觉功能的神经信号是未知。我的长期职业目标是记录神经回路如何源自大脑肠感知营养的能力。在NIH指导的研究科学家发展的支持下奖项 - K01，该提议的目的是描述一个可以用来用于的脑对肠神经电路在肠上皮上改变感觉翻译。这将在三个目标中实现： AIM 1。确定由肠道感觉细胞释放的神经递质和激素对兴奋性神经递质刺激的反应。体外类器官和分类的单细胞分析将是用于测量文化中的释放。这个目标将表明兴奋性神经递质可以刺激肠内分泌细胞中的水泡释放。目标2。将迷走神经刺激与感觉上皮细胞钙成像和电生理学评估迷走神经元突触到肠道感觉细胞上的功能连通性。这个目标演示一种功能连接，其中神经元增加了近端感觉细胞的兴奋小肠。 AIM 3。利用两种逆行（在鼻腔前）狂犬病病毒和顺行（前后）突触）单纯疱疹病毒，以追踪脑干和肠道之间的单突触连接感觉上皮细胞。此目标将建立一个解剖图，以了解脑干如何连接神经足类细胞。识别连接大脑和肠道的功能性神经回路将使人们能够理解内脏超敏反应的机制。我们与我的心理团队一起设计了为我提供必要的研究和专业培训的项目，以使我脱颖而出感觉神经胃肠病学领域的独立研究者。