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：
9494764
负责人：
ROBERTO Ariel GOMEZ
金额：
$ 57.97万
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 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9494764
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 frontier in vivo kidney cell kidney vascular structure mesangial cell novel precursor cell 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.

抽象的肾小球旁细胞释放的肾素通常足以维持血压和液体电解质然而，如果成年哺乳动物受到威胁体内平衡的操纵，就会顺利进行。肾小动脉沿线的肌细胞经历了显着的转变：它们从收缩性转变为一旦体内平衡达到，内分泌表型就获得合成和释放肾素的能力。重建后，转化的细胞再次成为平滑肌细胞，具有打开和关闭的能力。肾素表型似乎取决于转化细胞的发育历史：平滑肌细胞源自肾素前体，并在必要时保留合成肾素的记忆以恢复肾素表型的记忆位于基因组的哪个位置，它是如何构建的，随着细胞分化或改变生理状态，它如何被保留或消除尚不清楚。我们观察到肾素细胞拥有超级增强子（SE），大型基因组调控的动态簇是调节肾素表型重演的有力候选区域。假设是肾素表型的分子记忆驻留在染色质状态中小动脉细胞，由一组独特的 SE 介导，这些 SE 控制肾素细胞的身份和使用体内和体外谱系追踪、基因活性产生、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：目标 1. 检验以下假设：肾素细胞表型的获得伴随着建立独特的 SE，强制表达肾素谱系的基因。目标 2. 检验肾素 SE 调节肾素基因表达的假设，并通过染色质与其他基因的动态相互作用控制着肾素细胞的身份。了解血管细胞如何改变其身份是一个基本的生物学问题这些知识对多种肾病和肾外疾病的适用性可能会产生新的预防目标。肾素细胞命运的改变导致威胁心血管、肾脏和造血系统的疾病和功能障碍通过提供有关的重要新知识来协调多种稳态反应。小动脉细胞获得并维持其可塑性的机制，这是一个基本上尚未探索的前沿，这该提案有可能使患有肾脏和血管疾病以及高血压的儿童和成人受益。