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Human Lung Cell Atlas Project: genetic regulation of foetal and healthy adult lung cell states in 3D spatial resolution

人类肺细胞图谱项目：3D 空间分辨率下胎儿和健康成人肺细胞状态的遗传调控

基本信息

批准号：
MR/S035907/1
负责人：
Emma Rawlins
金额：
$ 56.57万
依托单位：
University of Cambridge
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2019
资助国家：
英国
起止时间：
2019 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FS035907%2F1
关键词：
Human Lung Cell Atlas Project

项目摘要

Cells are the functional units of our bodies. Different diseases are caused by changes in the types of cells in our bodies, or by changes in cell behaviour (cell state). The Human Cell Atlas is an international collaboration to characterise all cell types and states of the human body to understand how the healthy body functions. It will provide a reference map to identify cell changes that are associated with disease. We propose to study cell types and cell states in the healthy human lung to contribute to understanding of changes that occur in lung cancer and degenerative diseases, like pulmonary fibrosis and chronic obstructive pulmonary disease. Importantly, we will study the developing (foetal) human lung alongside the healthy adult lung. This will allow us to make comparisons between immature and mature cell states and, in the long-term, provide information that can be used as the basis for regenerative medicine. Cell type and cell state are defined by the different genes expressed in each cell. Single cell RNA sequencing technology, scRNA-seq for short, makes it possible to determine exactly which genes are active in any cell for thousands of cells in parallel. Using scRNA-seq will allow us to identify and characterise cells in the developing and adult human lung. We will build on our recent work in the adult lung that has identified an entirely new cell type, the ionocyte, to understand how different cells cooperate to build and maintain lung function. Firstly, we will carry out scRNA-seq in distinct spatial locations to identify all cell types of the developing lung. By looking at individual cells it becomes possible to identify characteristics that are associated with each cell. For example, whether it is still immature or has already acquired the characteristics of a more mature cell type. This makes scRNA-seq a very powerful tool to study human development. We will be asking how the human lungs develop during weeks 6-20 post-conception. We will compare our results from the foetus to how cell types and states are maintained in the adult human lung, leveraging funding that we have already obtained to study the adult tissue. Secondly, we will use a new single cell technology (single cell ATAC-seq) which will allow us to identify regions of DNA that control which genes are turned on or off in each cell. These experiments will help us to better define cell states and provide information about how these states are controlled. In the future, this knowledge will be used to find ways of modifying cell states to develop new treatments for disease. An atlas is not just a list, but also provides spatial information in the sense of a map. In the third part of our proposal we will place the identified cell types back into their spatial context. This is of particular importance for studying development and adult stem or progenitor cells, where the presence of neighbouring cells strongly influences behaviour. We will use spatial transcriptomics which allows the activity of all genes to be studied in space, but currently not at the resolution of individual cells. We will also use a technique called HCR, coupled with high performance microscopy, which measures fewer genes, but at single cell resolution. By combining these two techniques we will build a 3D map of the lung. Our work will generate large and complex data-sets that need to be integrated computationally. At the Wellcome Genome Campus we have world-leading computational expertise and infrastructure. We (Meyer) are already working in close collaboration with the Human Cell Atlas to maximise the benefits of this project for international biomedical research. This work will lay the foundations for a better understanding of many lung diseases. It will help us to interpret results from genetic studies of lung disease and impact on regenerative medicine and therapeutics development by revealing pathways controlling lung development and maintenance.

细胞是我们身体的功能单位。不同的疾病是由我们体内细胞类型的变化或细胞行为（细胞状态）的变化引起的。人类细胞图谱是一项国际合作，旨在了解人体的所有细胞类型和状态，以了解健康身体的功能。它将提供一个参考图谱，以识别与疾病相关的细胞变化。我们建议研究健康人肺中的细胞类型和细胞状态，以有助于了解肺癌和退行性疾病（如肺纤维化和慢性阻塞性肺病）中发生的变化。重要的是，我们将研究发育中的（胎儿）人肺以及健康的成人肺。这将使我们能够比较未成熟和成熟细胞状态，并从长远来看，提供可用作再生医学基础的信息。细胞类型和细胞状态由每个细胞中表达的不同基因定义。单细胞RNA测序技术，简称scRNA-seq，可以精确地确定哪些基因在任何细胞中的数千个细胞中是活跃的。使用scRNA-seq将使我们能够识别和鉴定发育中和成年人肺中的细胞。我们将在我们最近在成人肺中的工作的基础上，确定一种全新的细胞类型，离子细胞，以了解不同的细胞如何合作建立和维持肺功能。首先，我们将在不同的空间位置进行scRNA-seq，以识别发育中的肺的所有细胞类型。通过观察单个细胞，可以识别与每个细胞相关的特征。例如，它是否仍然不成熟或已经获得了更成熟细胞类型的特征。这使得scRNA-seq成为研究人类发育的一个非常强大的工具。我们将探讨人类的肺部在受孕后6-20周内是如何发育的。我们将比较我们从胎儿获得的结果与成人肺中细胞类型和状态的维持方式，利用我们已经获得的研究成人组织的资金。其次，我们将使用一种新的单细胞技术（单细胞ATAC-seq），这将使我们能够识别控制每个细胞中哪些基因被打开或关闭的DNA区域。这些实验将帮助我们更好地定义细胞状态，并提供有关如何控制这些状态的信息。在未来，这些知识将被用来寻找改变细胞状态的方法，以开发新的疾病治疗方法。地图集不仅仅是一个列表，而且还提供地图意义上的空间信息。在我们提案的第三部分，我们将把识别出的细胞类型放回它们的空间背景中。这对于研究发育和成体干细胞或祖细胞特别重要，因为邻近细胞的存在强烈影响行为。我们将使用空间转录组学，它允许在空间中研究所有基因的活性，但目前还不能以单个细胞的分辨率进行研究。我们还将使用一种称为HCR的技术，再加上高性能显微镜，它可以测量更少的基因，但在单细胞分辨率。通过结合这两种技术，我们将构建肺部的3D地图。我们的工作将产生大量复杂的数据集，这些数据集需要通过计算进行整合。在Wellcome Genome Campus，我们拥有世界领先的计算专业知识和基础设施。我们（Meyer）已经在与人类细胞图谱密切合作，以最大限度地提高该项目对国际生物医学研究的益处。这项工作将为更好地了解许多肺部疾病奠定基础。它将帮助我们解释肺部疾病的遗传研究结果，并通过揭示控制肺部发育和维持的途径对再生医学和治疗学发展产生影响。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics.

DOI：
10.1038/s41591-020-01227-z
发表时间：
2021-03
期刊：
NATURE MEDICINE
影响因子：
82.9
作者：
Muus, Christoph;Luecken, Malte D.;Eraslan, Gokcen;Sikkema, Lisa;Waghray, Avinash;Heimberg, Graham;Kobayashi, Yoshihiko;Vaishnav, Eeshit Dhaval;Subramanian, Ayshwarya;Smillie, Christopher;Jagadeesh, Karthik A.;Duong, Elizabeth Thu;Fiskin, Evgenij;Triglia, Elena Torlai;Ansari, Meshal;Cai, Peiwen;Lin, Brian;Buchanan, Justin;Chen, Sijia;Shu, Jian;Haber, Adam L.;Chung, Hattie;Montoro, Daniel T.;Adams, Taylor;Aliee, Hananeh;Allon, Samuel J.;Andrusivova, Zaneta;Angelidis, Ilias;Ashenberg, Orr;Bassler, Kevin;Becavin, Christophe;Benhar, Inbal;Bergenstrahle, Joseph;Bergenstrahle, Ludvig;Bolt, Liam;Braun, Emelie;Bui, Linh T.;Callori, Steven;Chaffin, Mark;Chichelnitskiy, Evgeny;Chiou, Joshua;Conlon, Thomas M.;Cuoco, Michael S.;Cuomo, Anna S. E.;Deprez, Marie;Duclos, Grant;Fine, Denise;Fischer, David S.;Ghazanfar, Shila;Gillich, Astrid;Giotti, Bruno;Gould, Joshua;Guo, Minzhe;Gutierrez, Austin J.;Habermann, Arun C.;Harvey, Tyler;He, Peng;Hou, Xiaomeng;Hu, Lijuan;Hu, Yan;Jaiswal, Alok;Ji, Lu;Jiang, Peiyong;Kapellos, Theodoros S.;Kuo, Christin S.;Larsson, Ludvig;Leney-Greene, Michael A.;Lim, Kyungtae;Litvinukova, Monika;Ludwig, Leif S.;Lukassen, Soeren;Luo, Wendy;Maatz, Henrike;Madissoon, Elo;Mamanova, Lira;Manakongtreecheep, Kasidet;Leroy, Sylvie;Mayr, Christoph H.;Mbano, Ian M.;McAdams, Alexi M.;Nabhan, Ahmad N.;Nyquist, Sarah K.;Penland, Lolita;Poirion, Olivier B.;Poli, Sergio;Qi, CanCan;Queen, Rachel;Reichart, Daniel;Rosas, Ivan;Schupp, Jonas C.;Shea, Conor, V;Shi, Xingyi;Sinha, Rahul;Sit, Rene, V;Slowikowski, Kamil;Slyper, Michal;Smith, Neal P.;Sountoulidis, Alex;Strunz, Maximilian;Sullivan, Travis B.;Sun, Dawei;Talavera-Lopez, Carlos;Tan, Peng;Tantivit, Jessica;Travaglini, Kyle J.;Tucker, Nathan R.;Vernon, Katherine A.;Wadsworth, Marc H.;Waldman, Julia;Wang, Xiuting;Xu, Ke;Yan, Wenjun;Zhao, William;Ziegler, Carly G. K.
通讯作者：
Ziegler, Carly G. K.

SOX9 maintains human foetal lung tip progenitor state by enhancing WNT and RTK signalling.

SOX9 通过增强 WNT 和 RTK 信号传导维持人胎儿肺尖祖细胞状态。