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Center for Quantitative Biology: A focus on "omics", from organisms to single cells Supplement 2

定量生物学中心：关注“组学”，从有机体到单细胞补充2

基本信息

批准号：
10853928
负责人：
MICHAEL L WHITFIELD
金额：
$ 77.13万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10853928
关键词：
Address Bioinformatics Biological Biological Assay Biology Biopsy Blood Cell Death Cell Separation Cells Centers of Research Excellence Clinical Research Communication Complex Creatinine DNA Methylation Data Disease Endothelium Epithelium Filtration Flare Freezing Glomerulonephritis Health Heterogeneity Immune In Situ Infiltration Inflammatory Injury Injury to Kidney Kidney Kidney Diseases Knowledge Lupus Lupus Nephritis Macrophage Mediating Methods Mission Molecular Morbidity - disease rate Myelogenous Myeloid Cells National Institute of General Medical Sciences Nature Organism Outcome Pathogenesis Pathogenicity Pathway interactions Patients Population Population Density Proteins Publishing Renal function Research Role Sampling Science Sorting Specificity Stimulus Structure Technology Testing Tissues Translational Research Tubular formation United States National Institutes of Health Urine burden of illness density direct application granulocyte immunopathology innovation interstitial kidney dysfunction monocyte mortality neutrophil non-invasive monitor novel novel strategies podocyte prevent recruit stem tool transcriptome sequencing transcriptomics

项目摘要

Project Summary / Abstract Macrophages and granulocytes (e.g., neutrophils) are considered key players in the pathogenesis of glomerular kidney injury, glomerulonephritis (GN). However, the intra-renal mechanisms and sub-cellular specificity by which these myeloid cells cause glomerular injury are not known. This large gap in knowledge stems from the limitations in approaches to capture and profile these highly heterogeneous cells. For example, neither normal density (NDN) nor low-density neutrophils (LDN), both implicated in GN, are not captured in scRNAseq studies of kidneys and urine due to the loss of these cells by sample freezing. Given their heterogeneity and importance in disease, implementing technologies that define myeloid populations in GN kidneys and how they interact with renal structural cells is critical for understanding their pathogenic role. Our spatial transcriptomic data reveal macrophages, NDNs, and LDNs in GN kidneys, with unique and shared spatial organizations. Using DNA methylation (DNAm) data from urine cells, we capture both macrophages and granulocytes in GN urine. The overall objectives in this proposal are to: (i) define myeloid populations in GN kidneys, (ii) identify pathogenic interactions between macrophages vs. granulocytes with renal structural cells, and (iii) implement urine DNAm assay to profile myeloid cells in GN. The central hypothesis is that glomerular interactions with LDNs reflect LN immunopathology and worse kidney function and that urine DNAm will allow a less invasive approach to evaluate the pathogenic myeloid populations. The hypothesis will be tested with two specific aims: 1) Define macrophage and granulocyte populations and their communication pathways with structural cells in GN kidneys and 2) Quantify and define kidney infiltrating myeloid populations in urine using DNAm. In Aim 1, single-cell spatial transcriptomics will be used to define in situ myeloid heterogeneity in GN kidneys by integrating bulk RNA-seq-derived transcriptomic signatures of sorted subpopulations. Pathogenic interactions with glomerular, interstitial, and tubular endothelial and epithelial structures will be defined. In Aim 2, macrophages and granulocytes will be quantified in urine using unique DNAm signatures in relation to kidney function. This research is innovative because it will propose molecular and cellular pathways involved in glomerular injury as well as introduce a novel approach to detect pathogenic cell populations via non-invasive urine analyses. This research is significant because it is expected to provide a scientific rationale for targeting specific myeloid populations in GN.

项目概要/摘要巨噬细胞和粒细胞（例如中性粒细胞）被认为是肾小球肾损伤、肾小球肾炎（GN）的发病机制。然而，肾内这些骨髓细胞引起肾小球损伤的机制和亚细胞特异性不知道。知识上的巨大差距源于捕获方法的局限性并对这些高度异质的细胞进行分析。例如，正常密度 (NDN) 和 scRNAseq 研究中未捕获与 GN 相关的低密度中性粒细胞 (LDN) 肾脏和尿液，因为样本冷冻会损失这些细胞。鉴于它们的异质性及其在疾病中的重要性，实施定义 GN 中骨髓细胞群的技术肾脏以及它们如何与肾结构细胞相互作用对于了解它们的关键致病作用。我们的空间转录组数据揭示了 GN 中的巨噬细胞、NDN 和 LDN 肾脏，具有独特且共享的空间组织。使用 DNA 甲基化 (DNAm) 数据我们从尿液细胞中捕获 GN 尿液中的巨噬细胞和粒细胞。整体该提案的目标是：(i) 定义 GN 肾脏中的骨髓细胞群，(ii) 确定巨噬细胞与粒细胞与肾结构细胞之间的致病相互作用，以及 (iii) 进行尿液 DNAm 测定来分析 GN 中的骨髓细胞。中心假设是肾小球与 LDN 的相互作用反映了 LN 免疫病理学和较差的肾功能尿液 DNAm 将允许采用侵入性较小的方法来评估致病性骨髓细胞人口。该假设将通过两个具体目标进行检验：1）定义巨噬细胞和 GN 肾脏中粒细胞群及其与结构细胞的通讯途径 2) 使用 DNAm 量化和定义尿液中肾脏浸润的骨髓细胞群。在目标 1 中，单细胞空间转录组学将用于定义 GN 中的原位骨髓异质性通过整合大量 RNA-seq 衍生的转录组特征来检测肾脏亚人群。与肾小球、间质和肾小管内皮细胞的致病相互作用上皮结构将被定义。在目标 2 中，将对巨噬细胞和粒细胞进行定量使用与肾功能相关的独特 DNAm 特征在尿液中进行检测。这项研究具有创新性因为它将提出参与肾小球损伤的分子和细胞途径以及引入一种通过非侵入性尿液检测致病细胞群的新方法分析。这项研究意义重大，因为它有望为以下问题提供科学依据：针对 GN 中的特定骨髓细胞群。

项目成果

期刊论文数量（29）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Pan-cancer evaluation of gene expression and somatic alteration data for cancer prognosis prediction.

泛伴对癌症预测的基因表达和体细胞改变数据的评估。

DOI：
10.1186/s12885-021-08796-3
发表时间：
2021-09-25
期刊：
BMC cancer
影响因子：
3.8
作者：
Zheng X;Amos CI;Frost HR
通讯作者：
Frost HR

mSphere of Influence: Learning Biology from the Radio.

DOI：
10.1128/msphere.00026-23
发表时间：
2023-02-21
期刊：
mSphere
影响因子：
4.8
作者：
通讯作者：

Asymmetric Partisan Voter Turnout Games.

DOI：
10.1007/s13235-021-00384-1
发表时间：
2021
期刊：
Dynamic games and applications
影响因子：
1.5
作者：
Guage C;Fu F
通讯作者：
Fu F

Nutrient Gradients Mediate Complex Colony-Level Antibiotic Responses in Structured Microbial Populations.

DOI：
10.3389/fmicb.2022.740259
发表时间：
2022
期刊：
FRONTIERS IN MICROBIOLOGY
影响因子：
5.2
作者：
Stevanovic, Mirjana;Boukeke-Lesplulier, Thomas;Hupe, Lukas;Hasty, Jeff;Bittihn, Philip;Schultz, Daniel
通讯作者：
Schultz, Daniel

Highly coordinated nationwide massive travel restrictions are central to effective mitigation and control of COVID-19 outbreaks in China.

DOI：
10.1098/rspa.2022.0040
发表时间：
2022-04
期刊：
PROCEEDINGS OF THE ROYAL SOCIETY A-MATHEMATICAL PHYSICAL AND ENGINEERING SCIENCES
影响因子：
3.5
作者：
Chen, Xingru;Fu, Feng
通讯作者：
Fu, Feng