Plasticity of renin cells in the kidney vasculature

肾血管系统中肾素细胞的可塑性

• 批准号: 10113595
• 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
• 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/10113595
• 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

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.

摘要： 肾小球旁细胞释放肾素通常足以维持血压和水电解质。 平衡。然而，如果成年哺乳动物受到威胁到动态平衡的操作， 肾小动脉沿线的肌肉细胞经历了一次显著的转变：它们从收缩转变为 一种内分泌表型，具有合成和释放肾素的能力。一旦动态平衡是 重新建立后，转化的细胞再次成为平滑肌细胞。能够打开和关闭 肾素表型似乎取决于转化细胞的发育历史：平滑肌细胞 肾素前体的后代，可能保留记忆，在必要时合成肾素以恢复 动态平衡。肾素表型的记忆在基因组中的什么位置，它是如何构建的， 当细胞分化或改变生理状态时，它是如何被保留或删除的，目前尚不清楚。 我们观察到肾素细胞具有超增强子(SE)，即大基因组调控的动态簇 这些区域是调节肾素表型重现的有力候选者。我们的整体 假设肾素表型的分子记忆存在于细胞的染色质状态 它是由一组独特的SE介导的，这些SE控制肾素细胞和 他们的后代。利用体内和体外谱系追踪、基因活性报告器、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.验证肾素细胞表型的获得伴随有 建立独特的SE，强制肾素谱系的基因表达。 目的2.验证肾素SE调节肾素基因表达的假说 染色质与其他基因的动态相互作用控制肾素细胞的特性。 了解血管细胞如何采用和转换它们的身份是一个基本的生物学问题 适用于多种肾脏和肾脏外疾病。这一知识可能会导致新的预防目标 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能力 来协调多种内环境平衡反应。通过提供基本的新知识来了解 小动脉细胞获得和维持其可塑性的机制，这是一个基本上未被探索的前沿。 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。