High resolution genomic and epigenomic mapping of the human salivary gland

人类唾液腺的高分辨率基因组和表观基因组图谱

基本信息

批准号：
10727190
负责人：
Rose-Anne Romano
金额：
$ 44.1万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10727190
关键词：
3-Dimensional ATAC-seq Adult Aging Area Autoimmune Diseases Biological Models Biological Process Biology Cell Communication Cells ChIP-seq Chemotherapy and/or radiation Chromatin Chromium Communication Complex Computer Analysis Data Data Set Digestion Disease Ecosystem Embryo Endothelium Enhancers Epithelium Experimental Models Female Fibroblasts Follow-Up Studies Food Functional disorder Gene Expression Gene Expression Profiling Gene Expression Regulation Gene Targeting Genes Genetic Genetic Diseases Genetic Transcription Genome Genomics Gland Goals Histones Homeostasis Human Immune Individual Inflammatory Investigation Knowledge Link Malignant Neoplasms Maps Microbe Minor salivary gland structure Molecular Multiomic Data Mus Neurons Normal tissue morphology Nucleic Acid Regulatory Sequences Nucleosomes Oral cavity Oral health Organ Organism Parotid Gland Pathologic Physiological Play Population Process Regulation Regulator Genes Research Resolution Resources Role Salivary Gland Diseases Salivary Glands Signal Pathway Signal Transduction Single Nucleotide Polymorphism Sjogren&apos s Syndrome Sublingual Gland Submandibular gland System Technology Testing Therapeutic Intervention Tissue-Specific Gene Expression Tissues Untranslated RNA Variant Work cell type computerized tools connectome epigenome epigenomics experimental study gene regulatory network genetic variant genome wide association study genome-wide analysis human disease improved in vivo innovation insight intercellular communication knowledge base male prevent progenitor programs promoter saliva secretion single-cell RNA sequencing therapeutically effective tool transcription factor transcriptome transcriptome sequencing transcriptomics

项目摘要

PROJECT SUMMARY A mechanistic and molecular examination of the differentiation programs and normal tissue homeostasis of the salivary glands (SG) is an important area of research since altered SG function is associated with multiple human disease conditions including Sjogren syndrome, cancer, and complications due to cancer chemo/radiation therapy. This necessitates an in-depth investigation of the complex ecosystem of SG that consists of a variety of epithelial and non-epithelial cell populations that cooperatively interact to facilitate SG function. The underlying molecular circuitry of the transcriptional and epigenomic gene-regulatory mechanisms that control SG biology, particularly as it pertains to individual cell types in the in vivo context of the human SG, however, is not very well-understood and thus presents a significant knowledge gap. Lack of this knowledge prevents a better understanding of principles of cell fate and lineage choices, cell-to-cell communication and transcriptional regulatory processes that are needed for guiding effective therapeutic interventions of human diseases. Our central hypothesis is that the establishment of the SG transcriptome, epigenome and gene regulatory networks is a dynamic process that results from reciprocal interactions between intracellular signaling pathways and the underlying hardwired genomic information of each cell-type. To test this hypothesis, three specific aims are proposed. Aim 1 is to generate single-cell RNA-sequencing (scRNA-seq), and scATAC-seq data from the same cells of the adult male and female SMG. The goals of Aim 2 are to use computational tools to define the cell fate trajectories and cell-to-cell communication systems that operate in the SG and identify crucial transcriptional regulators that define cell fate. Finally in Aim 3, the 3D chromatin state and the enhancer-promoter connectome map of the human SG will be established by HiChIP experiments. Such data will enable the establishment of the link between non-coding genetic variants and disease-associated genes that are relevant for disease such as Sjogren’s syndrome that primarily afflict the SG. This work is highly innovative and significant because our proposed use of cutting-edge technologies and sophisticated tools to examine fundamental transcriptional and epigenomic mechanisms of gene regulation and signaling pathways at a single cell resolution. Long term, such knowledge will substantially advance the fundamental understanding of SG biology and is anticipated to have a long-term impact on the treatment of complex genetic diseases of the SG.

项目概要分化程序和正常组织的机械和分子检查唾液腺 (SG) 的稳态是一个重要的研究领域，因为 SG 功能的改变与多种人类疾病相关，包括干燥综合征、癌症和并发症这需要对癌症化疗/放射治疗的复杂生态系统进行深入研究。 SG 由多种上皮细胞和非上皮细胞群组成，它们协同相互作用促进转录和表观基因组基因调控的 SG 功能。控制 SG 生物学的机制，特别是当它与体内环境中的个体细胞类型有关时然而，人类对 SG 的了解还不是很充分，因此存在严重的知识空白。这些知识阻碍了我们更好地理解细胞命运和谱系选择、细胞间的原理指导有效治疗所需的通讯和转录调节过程我们的中心假设是 SG 转录组的建立，表观基因组和基因调控网络是相互作用的结果的动态过程细胞内信号通路与每种细胞类型的潜在硬连线基因组信息之间的关系。为了检验这一假设，提出了三个具体目标：目标 1 是生成单细胞 RNA 测序。 (scRNA-seq) 和 scATAC-seq 数据来自成年男性和女性 SMG 的相同细胞。 2是使用计算工具来定义细胞命运轨迹和细胞间通讯系统在 SG 中运作并识别决定细胞命运的关键转录调节因子最后在目标 3（3D）中。将通过 HiChIP 建立人类 SG 的染色质状态和增强子-启动子连接组图这些数据将能够建立非编码遗传变异和非编码遗传变异之间的联系。与疾病相关的基因，例如干燥综合征，主要影响 SG。这项工作具有高度创新性和意义，因为我们建议使用尖端技术和检查基因调控的基本转录和表观基因组机制的复杂工具从长远来看，这些知识将大大推进单细胞分辨率的研究。对 SG 生物学的基本了解，预计将对 SG 的治疗产生长期影响 SG的复杂遗传病。