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了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 每个肾单位至少包含26种不同的细胞类型。然后，肾单位形成一个网络， 肾小球与各种管状节段、毛细血管、毛细血管和管周间隙相连。 这种动态的细胞网络不仅在个体之间变化，而且在整个肾脏中也是如此。 因为肾脏负责废物管理、电解质平衡、血压控制和红 血细胞生产，细胞组成或化学的差异可以极大地影响效率或疾病 进展到目前为止，还没有完全了解特定细胞数量的自然变化， 类型和它们各自在肾脏内的化学成分。关于这些指标如何与 性别和种族在这里，我们建议使用成像质谱（IMS）和共检测的组合， 索引多重免疫荧光（CODEX IF），以建立什么样的分子和细胞 人群构成正常、健康的肾脏，以及这些如何作为特定患者的功能而变化。 人口统计学虽然了解健康肾脏组织的细胞和分子组成是重要的， 就其本身而言，这一知识在不同疾病状态和表型的定义中具有明确的含义， 糖尿病肾病和器官衰竭我们预计通过两个关键目标来完成这些任务：1。 确定功能组织区域（如肾小球、皮质和髓质）的分子谱， 人类肾脏作为性别和种族的功能，使用成像质谱和2。探讨 髓质、皮质和肾盂内细胞类型的组成作为这些人口统计学的函数，使用 CODEX IF.简而言之，IMS允许可视化数百至数千种内源性代谢物和脂质， 而CODEX IF标记细胞类型和结构的复杂度高于传统IF方法。尽管两 方法本身提供了基本信息，我们可以协同联合收割机的数据，以获得 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， 人类病人最终，在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 或不同于平均值的独特细胞概况。这两个事件对于理解heathy都是必不可少的 其长期目标是确定这些相似性和差异如何导致疾病 发展和进步。虽然是一个大规模的项目，但我得到了许多科学领导人的帮助（见 支持）谁是投资于我的成功和项目的最终成功。我们的团队将建立一个 人类肾脏的全面化学和细胞图谱，重点是性别和种族。