Spatial Mapping of Proteomic and Transcriptional Signatures in Kidney Disease

肾脏疾病蛋白质组和转录特征的空间图谱

• 批准号: 10701891
• 负责人: WEN-YUAN E HSIEH
• 金额: $ 55.59万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701891
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Albuminuria; Anatomy; Atlases; Award; Bioinformatics; Biological; Biological Assay; Biological Sciences; Biopsy; Biopsy Specimen; Cancer Biology; Cells; Chronic Kidney Failure; Clinical Data; Colorado; Complement; Creatinine; Development; Diagnosis; Disease; Etiology; Expression Profiling; Funding; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genetic Complementation Test; Genetic Transcription; Goals; Human; Immune; Immunologist; Immunology; Immunotherapy; Injury; Interdisciplinary Study; Kidney; Kidney Diseases; Location; Maps; Medical; Methods; Molecular; Molecular Profiling; Morbidity - disease rate; Morphology; Multiplexed Ion Beam Imaging; Pathologic Processes; Pathologist; Pathway interactions; Patients; Pattern; Phenotype; Process; Proteins; Proteomics; Public Health; RNA; Renal function; Research; Resolution; Resources; Serum; Site; Standardization; Structure; Supportive care; Systems Biology; Technology; Testing; Therapeutic; Tissue atlas; Tissues; Translating; Universities; Widespread Disease; analytical method; anticancer research; candidate marker; cell type; experimental study; hemodynamics; high dimensionality; improved; injury and repair; innovation; insight; kidney biopsy; medical schools; mortality; multidimensional data; multiple omics; novel; novel diagnostics; novel therapeutic intervention; novel therapeutics; precision medicine; protein expression; proteomic signature; renal damage; therapeutic target; tool; transcriptome; transcriptomics; tumor

AKI and CKD are highly prevalent diseases that are associated with significant morbidity and mortality. Unfortunately, there are not currently any specific treatments for either of these conditions. Both diseases are caused by a range of underlying diseases and processes. AKI, for example, can result from hemodynamic, toxic, infectious, and immune insults to the kidney. In both AKI and CKD, the diagnosis is based on changes in the serum creatinine and albuminuria, but these tests do not discriminate among the various etiologies of injury. Thus, beyond detecting a reduction in kidney function, clinicians typically have little information regarding the underlying pathologic process. Better understanding of the cellular and molecular patterns in the kidneys of patients with AKI and CKD will provide key insights into these diseases and will lead to new diagnostic and therapeutic approaches. In recent years, multi-omics analyses have had a major impact on our understanding of several fields, such as cancer biology, and have supported the identification and development of new treatments. These same technologies could transform our understanding of AKI and CKD, particularly when spatial resolution is complemented with proteomic and transcriptomic cellular analyses. Although kidney biopsies are not usually performed in patients with AKI and CKD, biopsy samples obtained through the Kidney Precision Medicine Project (KPMP) offer a valuable opportunity to analyze kidney tissue using state-of-the-art high-dimensional multi-omic platforms. We propose to utilize complementary spatial protein and RNA technologies to generate comprehensive tissue atlases for AKI and CKD. We will pursue the following specific aims: Aim 1. Generate a kidney cellular map via phenotypic and functional protein expression profiling. We will analyze biopsies using Multiplexed Ion Beam Imaging (MIBI), which detects 40+ protein targets at single-cell resolution (250 nm) with tissue-specific spatial information. Aim 2. Generate a kidney morphological map via phenotypic and functional gene expression profiling. We will analyze biopsies using Visium Spatial Transcriptomics (ST), which provides the whole transcriptome with morphological context. Aim 3. Generate an integrated cellular and molecular protein and gene expression kidney atlas. We will apply statistical and bioinformatic approaches to integrate the results from Aims 1 and 2 to create a composite map of the cellular protein and transcriptional expression profiles in the kidney. To accomplish these goals, we have assembled a multidisciplinary research team that includes nephrologists, renal pathologists, immunologists, and experts on multi-omics systems biology analyses. The proposed experiments are expected to reveal subsets of AKI and CKD patients based on the patterns of cells and molecular pathways present in the kidney, and to support identification of novel candidate biomarkers and therapeutic targets.

AKI 和 CKD 是高度流行的疾病，与显着的发病率和死亡率相关。 不幸的是，目前还没有针对这两种情况的任何具体治疗方法。两种疾病 由一系列潜在疾病和过程引起。例如，AKI 可能是由于 对肾脏的血流动力学、毒性、感染性和免疫损伤。对于 AKI 和 CKD，诊断都是 基于血清肌酐和蛋白尿的变化，但这些测试并不区分 损伤的各种病因。因此，除了检测肾功能下降之外，临床医生通常还会 关于潜在病理过程的信息很少。更好地了解细胞和 AKI 和 CKD 患者肾脏的分子模式将为了解这些疾病提供重要见解 并将带来新的诊断和治疗方法。近年来，多组学分析 对我们对癌症生物学等多个领域的理解产生了重大影响，并支持了 识别和开发新的治疗方法。这些相同的技术可以改变我们的 了解 AKI 和 CKD，特别是当空间分辨率与蛋白质组学和 转录组细胞分析。尽管 AKI 患者通常不进行肾活检， 通过肾脏精准医学项目 (KPMP) 获得的 CKD、活检样本提供了有价值的信息 使用最先进的高维多组学平台分析肾脏组织的机会。我们 提议利用互补的空间蛋白质和RNA技术来生成综合组织 AKI 和 CKD 地图集。我们将追求以下具体目标： 目标 1. 生成肾脏细胞图谱 通过表型和功能蛋白表达谱。我们将使用多重离子分析活检 光束成像 (MIBI)，可通过组织特异性以单细胞分辨率 (250 nm) 检测 40 多个蛋白质靶标 空间信息。目标 2. 通过表型和功能基因生成肾脏形态图 表达分析。我们将使用 Visium 空间转录组学 (ST) 分析活检，它提供了 具有形态学背景的整个转录组。目标 3. 生成整合的细胞和分子蛋白质 和基因表达肾图谱。我们将应用统计和生物信息学方法来整合 根据目标 1 和 2 的结果创建细胞蛋白和转录表达的复合图 肾脏中的轮廓。为了实现这些目标，我们组建了一个多学科研究团队 包括肾脏病学家、肾脏病理学家、免疫学家和多组学系统生物学专家 分析。所提出的实验预计将根据以下结果揭示 AKI 和 CKD 患者的子集： 肾脏中存在的细胞和分子途径的模式，并支持新的识别 候选生物标志物和治疗靶点。