Project #2 Integrated single-nucleus multi-omics (ATAC-seq+RNA-seq or chromatin accessibility + RNA-seq) of human TGs

项目

• 批准号: 10806548
• 负责人: Hao Wu
• 金额: $ 136.43万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10806548
• 关键词: ATAC-seq; Atlases; Behavioral; Biological Assay; Biological Markers; Biology; Cell Nucleus; Cells; Cellular Assay; Chromatin; Collaborations; Collection; Complement; Complex; Cryopreserved Tissue; DNA Methylation; Data; Data Analyses; Data Set; Diagnosis; Dissociation; Drug Targeting; Electrophysiology (science); Epigenetic Process; Esthesia; Evaluation; Facial Pain; Foundations; Gene Expression; Gene Expression Profiling; Genes; Genetic Databases; Genetic Transcription; Genomics; Goals; Head; Headache; Headache Disorders; Health; Helping to End Addiction Long-term; Household; Human; Human Characteristics; International; Joints; Knowledge; Lead; Length; Maps; Measurement; Mediating; Messenger RNA; Methods; Methyltransferase; Migraine; Modality; Molecular; Morphology; Multiomic Data; Neuroglia; Neurons; Nuclear RNA; Pain; Pain Clinics; Patients; Physiological; Prevalence; RNA; Regulator Genes; Regulatory Element; Research Personnel; Resolution; Resources; Sampling; Spinal; Spinal Ganglia; Structure of trigeminal ganglion; System; Tissues; Trigeminal System; Uncertainty; United States; Universities; Untranslated RNA; Vertebral column; allodynia; cell type; chronic pain; chronic painful condition; comparative; effective therapy; epigenome; epigenomics; gene regulatory network; human RNA sequencing; in vivo; insight; migraine treatment; multidisciplinary; multiple omics; nervous system disorder; neuronal cell body; novel; novel strategies; response; single-cell RNA sequencing; somatosensory; transcriptome; transcriptome sequencing; transcriptomics

Migraine is a prevalent primary headache disorder that impacts one out of every four households in the United States. This complex neurologic disorder is mediated in part by alterations in trigeminal somatosensation, which manifests as head and facial pain and/or trigeminal allodynia. Despite its prevalence, there are currently limited effective treatments available for migraine, and our knowledge about human trigeminal system under baseline and migraine conditions are sparse. In response to RFA-NS-22-018, HEAL Initiative: Discovery and Functional Evaluation of Human Pain-associated Genes & Cells, we propose to form the Penn Human Precision Pain Center (Penn HPPC) to focus on elucidating molecular, cellular, epigenetic, and physiolog- ical profiles of human trigeminal ganglion (TG), which contains primary somatosensory neurons governing the head sensation, under baseline and migraine conditions. The Penn HPPC will be composed of Penn and inter- national investigators with multidisciplinary expertise. The PI, two co-PIs, and two co-Is are currently collaborat- ing on a single-soma deep RNA-seq of human dorsal root ganglion (DRG) neuron project, which form a strong foundation for this application. The Penn HPPC will contain three cores and perform three projects. Dr. Hao Wu, an expert in neuroepigenetics and single-cell genomics, will lead project 2 with support from Dr. Mingyao Li, the PI of the data core. This project aims to use two single-nucleus multi-omics assays, including the mas- sively parallel 10x Genomics multiome assay (3’ biased mRNA and open chromatin) and snmCAT-seq (full- length mRNA, open chromatin, and DNA methylation), to comprehensively map transcriptomic and epigenomic (chromatin accessibility and/or DNA methylation) profiles at single-nucleus resolution in control donors and those with migraine. In project 2, Aim 1 will focus on control trigeminal ganglion (TG) tissues, while Aim 2 will focus on TG tissues from "migraine" donors. The anticipated results will produce a comprehensive epigenetic and transcriptomic atlas to understand normal and abnormal trigeminal sensations associated with migraine. This rich resource may also lead to the discovery of new biomarkers for migraine diagnosis and novel potential drug targets for migraine treatment.

偏头痛是一种流行的原发性头痛疾病，影响着美国四分之一的家庭。 这种复杂的神经系统疾病部分是由三叉神经躯体感觉的改变介导的， 表现为头部和面部疼痛和/或三叉神经异常性疼痛，尽管其普遍存在，但目前仍存在。 偏头痛的有效治疗方法有限，而且我们对人类三叉神经系统的了解 基线和偏头痛情况很少 根据 RFA-NS-22-018，HEAL Initiative：发现和 人类疼痛相关基因和细胞的功能评估，我们建议成立宾夕法尼亚大学人类 精密疼痛中心 (Penn HPPC) 专注于阐明分子、细胞、表观遗传学和生理学 人类三叉神经节 (TG) 的轮廓，其中包含控制神经的初级体感神经元 Penn HPPC 将由 Penn 和 Inter- 组成。 具有多学科专业知识的国家研究人员目前正在合作。 正在进行人类背根神经节 (DRG) 神经元项目的单体深层 RNA 测序，该项目形成了强大的 Penn HPPC 将包含三个核心并执行三个项目。 神经表观遗传学和单细胞基因组学专家吴将在明耀博士的支持下领导项目2 Li，数据核心的 PI，该项目旨在使用两种单核多组学检测，包括 mas- 大规模并行 10x Genomics 多组分析（3' 偏向 mRNA 和开放染色质）和 snmCAT-seq（全 长度 mRNA、开放染色质和 DNA 甲基化），全面绘制转录组和表观基因组图谱 对照供体和那些供体的单核分辨率（染色质可及性和/或 DNA 甲基化）概况 在项目 2 中，目标 1 将侧重于控制三叉神经节 (TG) 组织，而目标 2 将侧重于控制三叉神经节 (TG) 组织。 预期的结果将产生全面的表观遗传学和 转录组图谱以了解与偏头痛相关的正常和异常三叉神经感觉。 丰富的资源还可能导致偏头痛诊断的新生物标志物和新的潜在药物的发现 偏头痛治疗的目标。