Plasticity of renin cells in the kidney vasculature

肾血管系统中肾素细胞的可塑性

基本信息

批准号：
10373943
负责人：
ROBERTO Ariel GOMEZ
金额：
$ 56.31万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10373943
关键词：
Adopted Adult Angiotensins Binding Biological Blood Pressure Blood Vessels Cardiovascular system Cell Differentiation process Cells Characteristics Child Chromatin Chromatin Structure Code Complex Cues DNA Dehydration Deposition Development Disease EP300 gene Electrolyte Balance Endocrine Enhancers Gene Expression Genes Genome Genomics Hematopoietic Histones Homeostasis Hypertension Image Imaging Techniques In Vitro Juxtaglomerular Cell Kidney Kidney Diseases Knowledge Lead Liquid substance Mammals Mediating Mediator of activation protein Medical Memory Molecular Mutation Nucleic Acid Regulatory Sequences Pathologic Pathology Pericytes Phenotype Physiological Proteins Recording of previous events Regulation Renin Reporter Genes Secure Smooth Muscle Myocytes Sodium Stress Testing Transferase Vascular Diseases arteriole cell transformation density epigenome editing frontier in vivo kidney cell kidney vascular structure mesangial cell novel precursor cell preservation prevent programs recruit response transcription factor

项目摘要

Abstract Release of renin by juxtaglomerular cells usually suffices to maintain blood pressure and fluid-electrolyte balance. However, if an adult mammal is subjected to manipulations that threaten homeostasis, smooth muscle cells along the renal arterioles undergo a remarkable transformation: they switch from a contractile to an endocrine phenotype acquiring the capacity to synthesize and release renin. Once homeostasis is reestablished, the transformed cells become smooth muscle cells again. The ability to switch on and off the renin phenotype seems to depend on the developmental history of the transformed cells: smooth muscle cells descend from renin precursors and may retain the memory to synthesize renin when necessary to regain homeostasis. Where in the genome the memory of the renin phenotype resides, how it is constructed, and how it is retained or erased as the cells differentiate or change physiological status is unknown. We observed that renin cells possess super-enhancers (SEs), dynamic clusters of large genomic regulatory regions that are strong candidates to regulate the reenactment of the renin phenotype. Our overall hypothesis is that the molecular memory of the renin phenotype resides in the chromatin state of the arteriolar cells and is mediated by a distinctive set of SEs that control the identity of renin cells and their descendants. Using in vivo and in vitro lineage tracking, reporters of gene activity, epigenome editing and chromatin imaging techniques, we propose to pursue the following interrelated hypotheses and aims: Aim 1. Test the hypothesis that acquisition of the renin cell phenotype is accompanied by the establishment of unique SEs that enforce the expression of genes from the renin lineage. Aim 2. Test the hypothesis that the renin SE regulates expression of the renin gene and through dynamic chromatin interactions with other genes controls renin cell identity. Understanding how vascular cells adopt and switch their identity is a fundamental biological question with applicability to multiple, renal and extra renal diseases. This knowledge may lead to novel targets to prevent renin cell fate changes that result in threatening cardiovascular, renal and hematopoietic diseases and inability to coordinate multiple homeostatic responses. By providing essential new knowledge regarding the mechanisms whereby arteriolar cells acquire and maintain their plasticity, a frontier basically unexplored, this proposal has the potential to benefit children and adults with kidney and vascular diseases and hypertension.

抽象的近齿状细胞释放肾素通常会遭受维持血压和流体 - 电解质平衡。但是，如果成年哺乳动物受到威胁体内稳态的操纵，则光滑沿着肾动物的肌肉细胞经历了显着的转变：它们从收缩切换到一种内分泌表型，既可以合成和释放肾素的能力。一旦体内平衡重新建立，转化后的细胞再次成为平滑肌细胞。打开和关闭的能力肾素表型似乎取决于转化细胞的发育历史：平滑肌细胞从肾素前体下降，并可能保留记忆以合成肾素的必要条件以恢复稳态。在基因组中，肾素表型住宅的记忆如何构造，以及由于细胞区分或变化身份状态而将其保留或擦除的方式尚不清楚。我们观察到肾素细胞具有超级增强剂（SES），大型基因组调节的动态簇是强大的候选者，以调节肾素表型的重新制定。我们的整体假设是肾素表型住宅的分子记忆中的染色质状态动脉细胞，由一组独特的SES介导，该SE控制肾素细胞和他们的后代。使用体内和体外谱系跟踪，基因活性的记者，表观基因组编辑和染色质成像技术，我们建议追求以下相互关联的假设和目标：目的1。检验以下假设：肾素细胞表型的获取是由建立独特的SES，从而实现了肾素谱系的基因表达。目标2。检验肾素SE调节肾素基因表达并通过动态染色质与其他基因的相互作用控制肾素细胞的身份。了解血管细胞如何采用和转换其身份是一个基本的生物学问题适用于多种，肾脏和额外的肾脏疾病。这些知识可能会导致新的目标以防止肾素细胞脂肪变化，导致威胁性心血管，肾脏和造血疾病和无能协调多个稳态响应。通过提供有关有关的基本知识大动脉细胞获得并维持其可塑性的机制，基本上是出乎意料的，这提案有可能使儿童和成人受益于肾脏和血管疾病以及高血压。