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。 蜂窝网络中的化学相互作用促进了器官系统的各种功能，并有助于 人类健康和疾病。人肾脏是一个复杂的器官，平均100万 单独包含至少26种不同细胞类型的肾单位。然后，肾单位形成一个由一个网络组成的网络 肾小球与各种管状片段，毛细血管，淋巴管和周围间质空间有关。 这个动态的蜂窝网络不仅因一个人而异，而且在整个肾脏本身之间。 因为肾脏负责废物管理，电解质平衡，血压控制和红色 血细胞产生，细胞组成或化学的差异会极大地影响效率或疾病 进展。迄今为止，尚未完全了解特定单元数量的自然差异 肾脏中的类型或各自的化学作用。关于这些指标与 性与种族。在这里，我们建议使用成像质谱法（IMS）和共同检测的组合 索引多路复用免疫荧光（法典IF），以建立一个分子和细胞的基线 种群构成正常，健康的肾脏，以及这些肾脏如何随特定患者的函数而变化 人口统计。虽然了解健康肾脏组织的细胞和分子成分很重要 就本身而言，这种知识对不同疾病状态和表型的定义具有明显的影响， 作为糖尿病性肾病和器官衰竭。我们通过两个关键目标预测完成这些任务：1。 确定功能组织区域（例如肾小球，皮质和髓质）的分子谱。 人类肾脏作为性和种族的功能，使用成像质谱和2。 髓质，皮层和肾骨盆内的细胞类型的组成，是这些人口统计的函数 法典如果。简而 而codex如果标签细胞类型和结构的丛为标记，则比传统方法更高。虽然两者兼而有之 方法独自提供基本信息，我们可以协同结合数据以获取 单个细胞类型的分子谱，以更好地解析组织区域之间的化学差异 人类患者。最终，将在每个组织和细胞中检测到分子 在所有测定的患者中保守的组成。此外，可能会有罕见的分子 或与平均值不同的唯一蜂窝曲线。这两个事件对于理解希思至关重要 以长期目标确定这些相似性和差异如何促进疾病 发展和发展。在一个大规模项目的同时，我得到了许多科学领袖的帮助（请参阅 支持我的成功和项目的最终成功。我们的团队将建立一个 人类肾脏的综合化学和细胞地图集，重点是性和种族。