Spatial Mapping of Proteomic and Transcriptional Signatures in Kidney Disease

AKI和CKD是高度流行的疾病，与显著的发病率和死亡率有关。 不幸的是，目前还没有任何针对这两种情况的特效治疗方法。这两种疾病 是由一系列潜在的疾病和过程引起的。例如，Aki可以由以下原因导致 血液动力学、毒性、感染性和免疫性对肾脏的侮辱。在AKI和CKD中，诊断都是 基于血清肌酐和蛋白尿的变化，但这些测试不区分 各种伤害的原因。因此，除了检测到肾功能下降外，临床医生通常还会 关于潜在的病理过程的信息很少。更好地了解蜂窝和 AKI和CKD患者肾脏中的分子模式将提供对这些疾病的关键见解 并将导致新的诊断和治疗方法。近年来，多重组学分析已经有了 对我们对几个领域的理解产生了重大影响，如癌症生物学，并支持 确定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和AKI患者通常不进行肾脏活检 CKD，通过肾脏精准医学项目(KPMP)获得的活检样本提供了宝贵的 利用最先进的高维多组学平台分析肾组织的机会。我们 建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。我们将使用多路复用离子来分析活检组织 束成像(MIBI)，以组织特异性的单细胞分辨率(250 Nm)检测40+蛋白质靶标 空间信息。目的2.利用表型基因和功能基因构建肾脏形态图谱 表情分析。我们将使用维西姆空间转录学(ST)来分析活检组织，它提供了 具有形态背景的完整转录组。目标3.产生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 来自AIMS 1和AIMS 2的结果创建了细胞蛋白质和转录表达的复合图 肾脏的侧写。为了实现这些目标，我们组建了一个多学科的研究团队， 包括肾病学家、肾脏病理学家、免疫学家和多组学系统生物学专家。 分析。拟议中的实验有望揭示AKI和CKD患者的亚群，基于 肾脏中存在的细胞和分子通路的模式，并支持鉴定新的 候选生物标志物和治疗靶点。

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.