Defining cellular mechanisms of chronic graft failure in transplanted hearts with single cell multi-omics

用单细胞多组学定义移植心脏慢性移植失败的细胞机制

• 批准号: 10611353
• 负责人: Ruli Gao
• 金额: $ 41.65万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-20 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10611353
• 关键词: Algorithms; Allografting; Biopsy; Biopsy Specimen; Biotechnology; Blood specimen; Cardiac; Cardiac Myocytes; Cause of Death; Cell Communication; Cell Lineage; Cell Nucleus; Cells; Chimerism; Chromatin; Chronic; Clinical; Collagen; Complex; Computing Methodologies; DNA; DNA Markers; DNA sequencing; Data; Detection; Disease; Endothelial Cells; Endothelium; Environment; Epigenetic Process; Etiology; Fibroblasts; Fibrosis; Freezing; Frequencies; Genetic Transcription; Genets; Genome; Genotype; Goals; Heart Transplantation; Heart failure; Human; Hypertrophy; Immune; Individual; Knowledge; Left Ventricular Mass; Life; Link; Measures; Mesenchymal; Metabolic Pathway; Methods; Mutate; Mutation; Organ; Outcome; Outcomes Research; Pathogenicity; Patients; Phenotype; Population; Process; RNA; Research; Role; Sampling; Series; System; Technology; Testing; Thick; Time; Transplant Recipients; Transplantation; Variant; Vascular Diseases; cell injury; cell type; chemokine; computerized tools; early onset; functional outcomes; graft failure; heart allograft; human tissue; improved; multiple omics; nanopore; new technology; new therapeutic target; novel; programs; single nucleus RNA-sequencing; single-cell RNA sequencing; success; synergism; therapeutic target; tool; transcriptome; vascular inflammation

Project Summary/Abstract Heart transplantation is a definitive treatment option for patients with end-stage heart failure. While short-term survival has made substantial improvements, long-term outcomes are limited by chronic graft failure. Cardiac allograft hypertrophy (CAH) is a clinical phenomenon referring to the gradual increase of left ventricular mass and wall thickness of cardiac grafts. CAH onset can occur as early as 2 months after transplantation, which often lead to progressive changes in cellular environment including cardiomyocytes hypertrophy and fibrosis and accumulate to graft failure in long term. The complete landscape of cellular system in transplant patients represents a major gap in knowledge. Single cell RNA sequencing (scRNA-seq) has emerged as powerful tool to analyze diverse cell types and cell states as well as pseudo-time topologies of single cells in complex organs, which however lacks the power to infer cell lineages that is important for identify the origins of pathogenic cells. In this project, we will develop a novel single cell multi-omics sequencing technology and several computational tools, which will enable simultaneous detection of cell lineage markers (i.e. DNAs) and cell fate markers (i.e. RNAs) from same cells. We will also distinguish donor and host identities for all cells to study their distinct roles in CAH that are largely unknown. We hypothesized that CAH is initiated by specific immune cell subtypes and driven by endothelial to mesenchymal transition that is fueled by enlarged cardiomyocytes. In aim 1, we will develop novel technology to define a unifying cell lineage and cell fate roadmap for cardiac cells. Aim 2 will dissect temporal changes of cellular components in transplanted hearts during CAH early onset. Aim 3 is to trace cell lineages during CAH progression with time-series single cell multi-omics. Successful completion of this project will lead to the identification of donor and host originated cell populations as novel therapeutic targets to extend the life of transplant patients.

项目概要/摘要 心脏移植是终末期心力衰竭患者的最终治疗选择。虽然短期 生存率取得了实质性改善，但长期结果受到慢性移植失败的限制。心脏 同种异体移植肥大（CAH）是指左心室质量逐渐增加的一种临床现象 和心脏移植物的壁厚度。 CAH 最早可在移植后 2 个月发生，这 经常导致细胞环境的进行性变化，包括心肌细胞肥大和纤维化 长期积累直至移植失败。移植患者细胞系统的完整景观 代表着知识上的重大差距。单细胞 RNA 测序 (scRNA-seq) 已成为强大的工具 分析复杂的不同细胞类型和细胞状态以及单个细胞的伪时间拓扑 器官，然而缺乏推断细胞谱系的能力，而细胞谱系对于识别细胞的起源很重要 致病细胞。在这个项目中，我们将开发一种新型的单细胞多组学测序技术并 多种计算工具，可同时检测细胞谱系标记（即 DNA）和 来自相同细胞的细胞命运标记（即 RNA）。我们还将区分所有细胞的供体和宿主身份 研究它们在 CAH 中的独特作用，但这些作用在很大程度上是未知的。我们假设 CAH 是由特定的 免疫细胞亚型并由内皮细胞向间质细胞转变驱动，而内皮细胞向间质细胞转变是由扩大的细胞推动的 心肌细胞。在目标 1 中，我们将开发新技术来定义统一的细胞谱系和细胞命运 心肌细胞的路线图。目标 2 将剖析移植心脏中细胞成分的时间变化 CAH 早期发作期间。目标 3 是利用时间序列单细胞追踪 CAH 进展过程中的细胞谱系 多组学。该项目的成功完成将导致捐赠者和宿主来源细胞的鉴定 人群作为延长移植患者生命的新治疗靶点。