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:
- 金额:$ 77.13万
- 依托单位:
- 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:
- 关键词:AddressBioinformaticsBiologicalBiological AssayBiologyBiopsyBloodCell DeathCell SeparationCellsCenters of Research ExcellenceClinical ResearchCommunicationComplexCreatinineDNA MethylationDataDiseaseEndotheliumEpitheliumFiltrationFlareFreezingGlomerulonephritisHealthHeterogeneityImmuneIn SituInfiltrationInflammatoryInjuryInjury to KidneyKidneyKidney DiseasesKnowledgeLupusLupus NephritisMacrophageMediatingMethodsMissionMolecularMorbidity - disease rateMyelogenousMyeloid CellsNational Institute of General Medical SciencesNatureOrganismOutcomePathogenesisPathogenicityPathway interactionsPatientsPopulationPopulation DensityProteinsPublishingRenal functionResearchRoleSamplingScienceSortingSpecificityStimulusStructureTechnologyTestingTissuesTranslational ResearchTubular formationUnited States National Institutes of HealthUrineburden of illnessdensitydirect applicationgranulocyteimmunopathologyinnovationinterstitialkidney dysfunctionmonocytemortalityneutrophilnon-invasive monitornovelnovel strategiespodocytepreventrecruitstemtooltranscriptome sequencingtranscriptomics
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.
项目总结/摘要
巨噬细胞和粒细胞(例如,中性粒细胞)被认为是
肾小球肾损伤的发病机制,肾小球肾炎(GN)。然而,肾内
这些髓样细胞引起肾小球损伤的机制和亚细胞特异性
不知道。这种巨大的知识差距源于获取方法的局限性,
并分析这些高度异质性的细胞。例如,正常密度(NDN)和
低密度中性粒细胞(LDN),两者都与GN有关,在scRNAseq研究中没有捕获,
肾脏和尿液,因为这些细胞因样品冷冻而损失。考虑到它们的异质性
和疾病的重要性,实施定义GN中骨髓群体的技术
肾脏以及它们如何与肾脏结构细胞相互作用对于了解它们的功能至关重要。
致病作用我们的空间转录组学数据揭示了GN中的巨噬细胞、NDN和LDN
肾脏,具有独特和共享的空间组织。使用DNA甲基化(DNAm)数据
从尿细胞中,我们捕获GN尿中的巨噬细胞和粒细胞。整体
该提案的目的是:(i)定义GN肾脏中的髓样细胞群,(ii)识别
巨噬细胞与粒细胞与肾结构细胞之间的致病性相互作用,以及
(iii)实施尿DNAm测定以分析GN中髓样细胞。核心假设是,
肾小球与LDN的相互作用反映了LN的免疫病理学和更差的肾功能,
尿液DNAm将允许一种侵入性较小的方法来评估致病性骨髓细胞,
人口。将以两个特定目的检验该假设:1)定义巨噬细胞,
肾小球肾炎中粒细胞群及其与结构细胞的通讯途径
和2)使用DNAm定量和确定尿中的肾浸润性骨髓群体。在目标1中,
单细胞空间转录组学将用于确定GN中的原位髓系异质性
通过整合大量RNA-seq衍生的转录组学特征,
亚群与肾小球、间质和肾小管内皮细胞的致病性相互作用,
将定义上皮结构。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DNA标记。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,
介绍一种通过非侵入性尿液检测致病细胞群新方法
分析。这项研究意义重大,因为它有望为
靶向GN中的特定髓样群体。
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:
- 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:
- 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:
- 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:
- 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:
- 影响因子:3.5
- 作者:Chen, Xingru;Fu, Feng
- 通讯作者:Fu, Feng
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MICHAEL L WHITFIELD其他文献
MICHAEL L WHITFIELD的其他文献
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{{ truncateString('MICHAEL L WHITFIELD', 18)}}的其他基金
Center for Quantitative Biology Administrative Core
定量生物学中心行政核心
- 批准号:
10434070 - 财政年份:2019
- 资助金额:
$ 77.13万 - 项目类别:
Center for Quantitative Biology: A focus on "omics", from organisms to single cells
定量生物学中心:关注“组学”,从有机体到单细胞
- 批准号:
10212411 - 财政年份:2019
- 资助金额:
$ 77.13万 - 项目类别:
Center for Quantitative Biology Administrative Core
定量生物学中心行政核心
- 批准号:
10212412 - 财政年份:2019
- 资助金额:
$ 77.13万 - 项目类别:
Center for Quantitative Biology Administrative Core
定量生物学中心行政核心
- 批准号:
10663279 - 财政年份:2019
- 资助金额:
$ 77.13万 - 项目类别:
SARS-CoV-2 Surveillance Studies and Genome Sequencing in Rural New England
新英格兰农村地区的 SARS-CoV-2 监测研究和基因组测序
- 批准号:
10381159 - 财政年份:2019
- 资助金额:
$ 77.13万 - 项目类别:
Center for Quantitative Biology: A focus on "omics", from organisms to single cells
定量生物学中心:关注“组学”,从有机体到单细胞
- 批准号:
10434069 - 财政年份:2019
- 资助金额:
$ 77.13万 - 项目类别:
Enabling single molecule spatial transcriptomics with the Vizgen MERSCOPE in situ hybridization solution at Dartmouth and beyond
在达特茅斯及其他地区使用 Vizgen MERSCOPE 原位杂交解决方案实现单分子空间转录组学
- 批准号:
10581931 - 财政年份:2019
- 资助金额:
$ 77.13万 - 项目类别:
Center for Quantitative Biology: A focus on "omics", from organisms to single cells
定量生物学中心:关注“组学”,从有机体到单细胞
- 批准号:
10663278 - 财政年份:2019
- 资助金额:
$ 77.13万 - 项目类别:
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