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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：
9897536
负责人：
ROBERTO Ariel GOMEZ
金额：
$ 56.11万
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/9897536
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.

文摘