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Harnessing endothelial cell transdifferentiation for cardiovascular therapy

利用内皮细胞转分化进行心血管治疗

基本信息

批准号：
10513527
负责人：
Brad Morrison
金额：
$ 40.87万
依托单位：
BOISE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10513527
关键词：
Acinar Cell Adult Back Bar Codes Beta Cell Blood Vessels Bone Marrow Busulfan Capsid Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Cause of Death Cell Lineage Cells Cellular biology Clinical Coupled Cytoplasm Cytoplasmic Granules DNA cassette Data Dependovirus Development Duodenum Endothelial Cells Endothelium Engineering Enterobacteria phage P1 Cre recombinase Enterocytes Event Genetic Hair follicle structure Hepatocyte Hippocampus (Brain)Histologic Homeostasis In Situ Hybridization Intravenous Islets of Langerhans Kidney Knowledge Label Lead Lentivirus Lentivirus Vector Mammals Mediating Methods Microglia Morphologic artifacts Mus Muscle Fibers Mutation Nature Neurons Outcome Pancreas Pathology Population Process Proteins Purkinje Cells Research Infrastructure Resources Serotyping Source Stomach System Tamoxifen Testing Tissues Transgenes Transgenic Mice Tubular formation Universities Viral Viral Proteins Viral Vector Virus Wild Type Mouse Work base cadherin 5 cell type crypt cell endothelial stem cell experience extracellular vesicles follow-up gene therapy genetic technology improved in vivo insight interest intravenous injection novel novel strategies stem cells therapeutic gene tool transdifferentiation transgene delivery transmission process undergraduate research

项目摘要

Cardiovascular disease is the leading cause of death, so recent efforts have focused on using emerging genetic technologies to remediate cardiac and vascular pathologies. These efforts are largely based on a growing number of studies, including our preliminary data, that have observed transgene delivery to cardiac myocytes via intravenous injection of a viral vector. However, to date, there is no empirically backed rationale for any mechanism underlying this important finding. My lab has focused on the prospect of endothelial cell transdifferentiation for many years and accrued evidence that this process exists in adult mice and may be responsible for the homeostasis of diverse cell types. Our preliminary data coupled with our proposed approach will determine whether cardiac myocyte labeling is the result of a transdifferentiation event (endothelial cell or otherwise) or the product of extracellular vesicle transfer. This work will also confirm whether the source of this labeling is endothelial cells. We are also interested in determining the nature of intravenous transgene delivery to other cell types, which could yield information about the localization of endothelial cell transdifferentiation to discrete niches. The existence of such niches could have important implications for enhancing the vascular pathology of those regions. This work will be undertaken using separate state-of-the-art cell lineage tracing strategies that encompass virus, protein, and cell-based methods. The answers provided by this study will help guide efforts for cardiac genetic therapy, advance our understanding of endothelial cell biology, and provide potentially new insights into cardiovascular disease.

心血管疾病是导致死亡的主要原因，因此最近的努力集中在使用新兴的基因技术来治疗心脏和血管疾病。这些努力主要是基于越来越多的研究，包括我们的初步数据，已经观察到转基因通过静脉内注射病毒载体递送至心肌细胞。然而，到目前为止，没有这一重要发现背后的任何机制的经验支持的理由。我的实验室专注于关于内皮细胞转分化的前景的研究已经进行了很多年，并积累了证据表明，这一过程存在于成年小鼠中，可能负责不同细胞类型的稳态。我们初步数据加上我们提出的方法将确定心肌细胞标记是否是转分化事件（内皮细胞或其他）的结果或细胞外分化的产物。囊泡转移这项工作也将确认这种标记的来源是否是内皮细胞。我们也对确定静脉内转基因递送到其他细胞类型的性质感兴趣，可以产生关于内皮细胞转分化到离散小生境的定位的信息。这些小生境的存在可能对增强血管病理学有重要意义这些地区。这项工作将采用单独的国家最先进的细胞谱系追踪包括病毒，蛋白质和细胞为基础的方法的战略。这项研究提供的答案将有助于指导心脏基因治疗的努力，促进我们对内皮细胞生物学的理解，并为心血管疾病提供潜在的新见解。