权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Pbx1 transcriptional regulation in renal vascular mural cells

肾血管壁细胞中Pbx1的转录调控

基本信息

批准号：
9314809
负责人：
DORIS A HERZLINGER
金额：
$ 16.95万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-15 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9314809
关键词：
3-Dimensional Ablation Adult Angiogenic Factor Animals Antibodies Architecture Attenuated Binding Biological Assay Blood Blood Vessels Blood flow Cell Differentiation process Cell Lineage Cell Surface Proteins Cell physiology Cells Cessation of life Collaborations Contractile Proteins Data Defect Development End stage renal failure Endothelium Epithelial Erythrocytes Exhibits Fibrosis Frequencies Functional Imaging Functional disorder Gene Dosage Genes Genetic Genetic Transcription Genotype Homeostasis Image Imaging Techniques Immunofluorescence Microscopy In Situ Hybridization In Vitro Injury Kidney Knockout Mice Label Measures Mediating Microscopic Microscopy Modeling Molecular Morphogenesis Mus Mutation Nephrons Pattern Pericytes Phenocopy Phenotype Physiology Play Process Property Protocols documentation Publications Publishing Regional Blood Flow Regulation Renal Blood Flow Renal Tissue Renal function Reporter Role Semaphorin-3A Shunt Device Signal Pathway Sorting - Cell Movement Structure Structure of glomerular mesangium Techniques Testing Tissue Engineering Transcriptional Regulation Trees Ureteral obstruction Vascular Smooth Muscle Vascularization Venous Venous Malformation contrast enhanced design differential expression hemodynamics in vivo injured kidney cortex kidney vascular structure mouse model multi-photon mutant novel novel therapeutics overexpression premature programs protein expression pup research study response response to injury transcription factor transcriptome transcriptome sequencing vascular bed vasoactive agent

项目摘要

SUMMARY Hemodynamic forces play a crucial role in renal physiology and pathophysiology but the cellular and molecular mechanisms controlling the development of the specialized properties of the renal vascular bed remain poorly understood. We recently discovered that the Foxd1 lineage, which differentiates into pericytes, vascular smooth muscle, and the glomerular mesangium, plays a fundamental role in this process. Specifically, conditional ablation of the TALE transcription factor, Pbx1, in this lineage results in gross renal arterial patterning defects and premature death of mutant pups. Strikingly, conditional Pbx1 ablation does not markedly perturb renal epithelial morphogenesis. These data suggest that ablation of Pbx1 in the Foxd1 lineage reveals vascular patterning defects arising solely from the abnormal function of cells derived from the Foxd1 lineage. Using murine genetics and state-of-the art functional imaging techniques in collaboration with Dr. Peti-Peterdi, we will investigate the role of Pbx1 transcriptional regulation in the Foxd1 lineage. In Aim 1, we will determine how conditional Pbx1 ablation perturbs renal hemodynamics. Aim 2 will investigate the role of Pbx1-TR regulation in controlling the secretion of angiogenic factors by Foxd1-derivatives. Finally, in Aim 3 we will test whether Pbx1 transcriptional regulation in the mature kidney plays a role in its response to injury. Results of these studies investigating the mechanisms of gross renal vascular patterning will provide important clues for the design of protocols to functionally vascular renal tissues engineered in vitro and may inspire novel techniques to attenuate renal fibrosis, a major cause of end stage renal disease.

概括血流动力学在肾脏生理学和病理生理学中起着至关重要的作用，但细胞和控制特殊性质发展的分子机制肾血管床仍然知之甚少。我们最近发现 Foxd1 谱系，分化为周细胞、血管平滑肌和肾小球系膜，在此过程中发挥着基础性作用。具体来说，有条件的 TALE 消融该谱系中的转录因子 Pbx1 会导致肾动脉模式缺陷和突变幼崽过早死亡。引人注目的是，有条件的 Pbx1 消融并不显着扰乱肾上皮形态发生。这些数据表明 Foxd1 中 Pbx1 的消融谱系揭示了仅由细胞功能异常引起的血管图案缺陷源自 Foxd1 谱系。使用小鼠遗传学和最先进的功能成像与 Peti-Peterdi 博士合作的技术，我们将研究 Pbx1 的作用 Foxd1 谱系中的转录调控。在目标 1 中，我们将确定 Pbx1 的条件如何消融会扰乱肾脏血流动力学。目标 2 将研究 Pbx1-TR 调节在通过 Foxd1 衍生物控制血管生成因子的分泌。最后，在目标 3 中我们将测试成熟肾脏中的 Pbx1 转录调控是否在其对受伤。这些研究的结果调查了大体肾血管模式的机制将为功能性血管肾组织的方案设计提供重要线索体外工程设计，可能会激发减轻肾纤维化的新技术，肾纤维化是一个主要原因终末期肾病。