Defining regional anatomical variation in cellular composition, transcriptome and epigenome in the human kidney

定义人肾细胞组成、转录组和表观基因组的区域解剖变异

• 批准号: MR/S035842/1
• 负责人: Menna Clatworthy
• 金额: $ 56.28万
• 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%2FS035842%2F1
• 关键词: Defining; regional; anatomical; variation; cellular

The kidneys play a vital role in cleaning the blood and controlling the body's water balance. Unfortunately, their function may be affected by a number of common diseases including infection, diabetes, damage by reduced blood supply and high blood pressure or the toxic effects of some drugs. Kidney failure can be treated with dialysis or transplant, but both (particularly dialysis) are associated with reduced life expectancy. The individual building blocks of the kidneys are called cells, and each kidney has hundreds of millions of cells that work in groups that have a similar function. The interaction of individual cells, and groups of cells, is required for normal organ function. Among the different cell types that reside in the kidney are immune cells, the body's defence system cells. These sentinels stand guard and alert the body to local problems by starting an inflammatory response. They also play an important role in tissue healing and repair. Because of their job of excreting waste and controlling water balance, the kidneys make an unusual and difficult environment for immune cells; some parts of the kidney have a very high salt concentration, so the cells are living in a salt marsh and this can affect their function. At present, we don't fully understand the different types of cells that make up the kidney, how many different of immune cells live there, how they are positioned relative to each other, or whether the extreme environment of some parts of the kidney changes how the cells behave. Answering these questions will help us to determine how cell function goes wrong in kidney diseases and will therefore allow the development of better treatments.Our aim is to make a cell map of the human kidney. We will take two experimental approaches: The first is to take a piece of kidney, mash it up to break up the cell groups so that we can analyse individual cells. Different cells have different functions and identification marks because of differences in which parts of their genetic material (called genes) are translated into proteins. Protein are the molecules that mark a cell and allow it to function. Every cell contains tens of thousands of proteins, giving it a unique signature, but these are hard to measure in a single cell. However, we can measure the molecule that acts as an intermediate between genes and proteins, this is called messenger RNA or mRNA. In the past 10 years, technology has advanced such that we can measure thousands of mRNA molecules in a single cell, this is what we plan to do with the mashed kidney samples that we will take from 6 different regions across the human kidney.Our second experimental approach is to take a piece of kidney and keep it intact so that the relationship of the cells in space is maintained. We will then make slices of the piece of kidney so that they are thin enough to be seen under a microscope. We will use the mRNA information from our first experiment to identify a small number of markers that can be visualised by the microscope using probes that are fluorescently labeled. This will allow us to investigate the position of cells relative to each other and how different cells in both the adult and developing kidney provide support or a 'niche' for immune cells.Making a complete map of cells in the normal kidney will provide a critical reference atlas that will help researchers in the future to understand which cells become abnormal in different kidney diseases and how cell interactions are disrupted in disease. This will provide invaluable information to help identify new treatment targets.

肾脏在清洁血液和控制身体的水平衡方面起着至关重要的作用。不幸的是，它们的功能可能会受到一些常见疾病的影响，包括感染、糖尿病、血液供应减少和高血压造成的损害或某些药物的毒性作用。肾衰竭可以通过透析或移植来治疗，但两者（特别是透析）都与预期寿命缩短有关。肾脏的各个组成部分被称为细胞，每个肾脏都有数亿个细胞，这些细胞在具有类似功能的群体中工作。单个细胞和细胞群的相互作用是正常器官功能所必需的。在肾脏中存在的不同细胞类型中，有免疫细胞，即人体的防御系统细胞。这些哨兵站岗，并通过启动炎症反应来提醒身体注意局部问题。它们还在组织愈合和修复中发挥重要作用。由于它们的排泄废物和控制水平衡的工作，肾脏为免疫细胞创造了一个不寻常和困难的环境;肾脏的某些部分具有非常高的盐浓度，因此细胞生活在盐沼中，这会影响它们的功能。目前，我们还不完全了解组成肾脏的不同类型的细胞，有多少不同的免疫细胞生活在那里，它们如何相互定位，或者肾脏某些部分的极端环境是否会改变细胞的行为。弄清这些问题将有助于我们确定细胞功能在肾脏疾病中是如何出错的，从而有助于开发更好的治疗方法。我们的目标是绘制人类肾脏的细胞图谱。我们将采取两种实验方法：第一种是取一片肾脏，将其捣碎以分解细胞群，这样我们就可以分析单个细胞。不同的细胞具有不同的功能和识别标记，因为它们的遗传物质（称为基因）的部分被翻译成蛋白质。蛋白质是标记细胞并使其发挥功能的分子。每个细胞都含有成千上万的蛋白质，这给了它一个独特的特征，但这些很难在单个细胞中测量。然而，我们可以测量作为基因和蛋白质之间的中间体的分子，这被称为信使RNA或mRNA。在过去的10年里，技术已经发展到可以测量单个细胞中成千上万的mRNA分子，这就是我们计划从人类肾脏的6个不同区域采集的捣碎的肾脏样本所做的事情。我们的第二个实验方法是取一片肾脏并保持其完整，以便保持空间中细胞的关系。然后，我们将肾脏切片，使它们足够薄，可以在显微镜下看到。我们将使用来自我们第一个实验的mRNA信息来识别少量标记物，这些标记物可以通过显微镜使用荧光标记的探针进行可视化。这将使我们能够研究细胞之间的相对位置，以及成年和发育中的肾脏中不同细胞如何为免疫细胞提供支持或“生态位”。绘制正常肾脏中细胞的完整图谱将提供重要的参考图谱，这将有助于未来的研究人员了解哪些细胞在不同的肾脏疾病中变得异常，以及疾病中细胞相互作用如何被破坏。这将提供宝贵的信息，以帮助确定新的治疗目标。

项目成果

Cells of the human intestinal tract mapped across space and time.

• DOI: 10.1038/s41586-021-03852-1
• 发表时间: 2021-09
• 期刊: Nature
• 影响因子: 64.8
• 作者: Elmentaite R;Kumasaka N;Roberts K;Fleming A;Dann E;King HW;Kleshchevnikov V;Dabrowska M;Pritchard S;Bolt L;Vieira SF;Mamanova L;Huang N;Perrone F;Goh Kai'En I;Lisgo SN;Katan M;Leonard S;Oliver TRW;Hook CE;Nayak K;Campos LS;Domínguez Conde C;Stephenson E;Engelbert J;Botting RA;Polanski K;van Dongen S;Patel M;Morgan MD;Marioni JC;Bayraktar OA;Meyer KB;He X;Barker RA;Uhlig HH;Mahbubani KT;Saeb-Parsy K;Zilbauer M;Clatworthy MR;Haniffa M;James KR;Teichmann SA
• 通讯作者: Teichmann SA

The gut-meningeal immune axis: Priming brain defense against the most likely invaders.

肠道-脑膜免疫轴：启动大脑防御最有可能的入侵者。

• DOI: 10.17863/cam.82841
• 发表时间: 2022
• 作者: Di Marco Barros R

Early human lung immune cell development and its role in epithelial cell fate

早期人肺免疫细胞发育及其在上皮细胞命运中的作用

• DOI: 10.1101/2022.12.13.519713
• 发表时间: 2022
• 作者: Barnes J

Cells of the human intestinal tract mapped across space and time

人类肠道细胞跨越空间和时间的映射

• DOI: 10.17863/cam.76097
• 发表时间: 2021
• 作者: Elmentaite R