Investigating Molecular and Cellular Heterogeneity within the Human Kidney using Multimodal Imaging Approaches

使用多模态成像方法研究人肾脏内的分子和细胞异质性

• 批准号: 10386620
• 负责人: Elizabeth Kathleen Neumann
• 金额: $ 2.45万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10386620
• 关键词: Affect; Age; Antibodies; Architecture; Atlases; Bar Codes; Biological Assay; Blood capillaries; Cells; Cellular Structures; Chemicals; Chemistry; Complex; Data; Data Set; Detection; Development; Diabetic Nephropathy; Disease; Disease Progression; Distal; Duct (organ) structure; Electrolyte Balance; Endothelium; Erythrocytes; Ethnic Origin; Event; Excision; Fluorescence Microscopy; Goals; Health; Heterogeneity; Histologic; Human; Human BioMolecular Atlas Program; Immunofluorescence Immunologic; Immunohistochemistry; Individual; Intrinsic factor; Kidney; Knowledge; Label; Learning; Letters; Link; Lipids; Lymphatic; Masks; Measures; Methods; Modality; Molecular; Molecular Profiling; Multimodal Imaging; Nephrons; Oligonucleotides; Operative Surgical Procedures; Organ; Organ failure; Patients; Peptides; Phenotype; Population; Production; Proteins; Race; Renal function; Renal pelvis; Role; Severities; Spatial Distribution; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Stains; Statistical Data Interpretation; Structure; Sum; Therapeutic Intervention; Tissues; Tubular formation; Visualization; Waste Management; blood pressure control; body system; cell type; demographics; experimental study; histological stains; human disease; image processing; imaging approach; indexing; interstitial; kidney cell; kidney imaging; mass spectrometric imaging; metabolic profile; metabolomics; microscopic imaging; multiplexed imaging; sex; success; targeted imaging; wasting

PROJECT SUMMARY. The chemical interplay within cellular networks facilitates diverse functions of organ systems and contributes to human health and disease. The human kidney is a complex organ composed of an average of one million nephrons that individually contain at least 26 distinct cell types. Nephrons then form a network consisting of a glomerulus that is linked to various tubular segments, capillaries, lymphatics, and peritubular interstitial spaces. This dynamic cellular network not only varies from one individual to another but throughout the kidney itself. Because the kidney is responsible for waste management, electrolyte balance, blood pressure control, and red blood cell production, differences in cellular composition or chemistry can greatly impact efficiency or disease progression. To date, there is not complete understanding of the natural variance in the numbers of specific cell types nor their respective chemistries within the kidney. Even less is known about how these metrics relate to sex and race. Here, we propose to use a combination of imaging mass spectrometry (IMS) and co-detection by indexing multiplexed immunofluorescence (CODEX IF) to establish a baseline of what molecules and cellular populations constitute a normal, healthy kidney as well as how these change as a function of specific patient demographics. While understanding the cellular and molecular constituents of healthy kidney tissue is important by itself, this knowledge has clear implications in the definition of different disease states and phenotypes, such as diabetic nephropathy and organ failure. We predict accomplishing these tasks through two key aims: 1. determine the molecular profiles of functional tissue regions (e.g. glomeruli, cortex, and medulla) within the human kidney as the function of sex and race using imaging mass spectrometry and 2. investigate the composition of cell types within the medulla, cortex, and renal pelvis as a function of these demographics using CODEX IF. In brief, IMS allows visualization of hundreds to thousands of endogenous metabolites and lipids, while CODEX IF labels cell types and structures at a higher plexity than traditional IF methods. Though both approaches provide essential information on their own, we can synergistically combine the data to obtain molecular profiles of individual cell types to better parse the chemical differences between regions of tissue and human patients. Ultimately, there will be molecules that are detected within every tissue as well as cell compositions that are conserved among all the assayed patients. Additionally, there will likely be rare molecules or unique cellular profiles that differ from the average. Both events are essential for understanding heathy function with a longer-term goal of determining how these similarities and differences contribute to disease development and progression. While a large-scale project, I am aided by many scientific leaders (see letters of support) who are invested in my success and the ultimate success of the project. Our team will build a comprehensive chemical and cellular atlas of the human kidney with emphasis on sex and race.

项目摘要。 细胞网络内的化学相互作用促进器官系统的多种功能，并有助于 人类健康和疾病。人体肾脏是一个复杂的器官，平均由一百万个组成 肾单位分别包含至少 26 种不同的细胞类型。然后肾单位形成一个网络，其中包括 肾小球与各个肾小管段、毛细血管、淋巴管和肾小管周围间隙相连。 这种动态的细胞网络不仅因人而异，而且遍及肾脏本身。 因为肾脏负责废物管理、电解质平衡、血压控制和红色 血细胞生成、细胞成分或化学成分的差异会极大地影响效率或疾病 进展。迄今为止，对特定细胞数量的自然方差还没有完全了解 类型及其在肾脏内各自的化学成分。人们对这些指标之间的关系知之甚少。 性别和种族。在这里，我们建议结合使用成像质谱（IMS）和联合检测 索引多重免疫荧光 (CODEX IF) 以建立分子和细胞的基线 人群构成了正常、健康的肾脏，以及这些肾脏如何随着特定患者的功能而变化 人口统计。了解健康肾组织的细胞和分子成分很重要 就其本身而言，这一知识对不同疾病状态和表型的定义具有明确的影响，例如 如糖尿病肾病和器官衰竭。我们预测通过两个关键目标来完成这些任务：1. 确定功能组织区域（例如肾小球、皮质和髓质）的分子谱 使用成像质谱法研究人类肾脏作为性别和种族的函数，并 2. 研究 髓质、皮质和肾盂内细胞类型的组成作为这些人口统计的函数，使用 食品法典委员会如果。简而言之，IMS 允许数百到数千种内源代谢物和脂质的可视化， 而 CODEX IF 标记细胞类型和结构的复杂性比传统 IF 方法更高。虽然两者 方法本身提供了必要的信息，我们可以协同地组合数据以获得 单个细胞类型的分子图谱，以更好地解析组织区域和区域之间的化学差异 人类患者。最终，每个组织和细胞中都会检测到分子 在所有测定的患者中保守的组合物。此外，可能会有稀有分子 或不同于平均水平的独特的细胞特征。这两个事件对于理解健康都是至关重要的 具有确定这些相似性和差异如何导致疾病的长期目标的功能 发展和进步。虽然是一个大型项目，但我得到了许多科学领袖的帮助（参见信件） 支持）他们为我的成功和项目的最终成功进行了投资。我们的团队将打造一个 人类肾脏的综合化学和细胞图谱，重点关注性别和种族。