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

Renal vascular remodeling and arteriogenesis: cues from smooth muscle progenitor cells

肾血管重塑和动脉生成：来自平滑肌祖细胞的线索

基本信息

批准号：
10116371
负责人：
Ondine B Cleaver
金额：
$ 35.25万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10116371
关键词：
Ablation Acute Renal Failure with Renal Papillary Necrosis Address Adult Affect American Blood Vessels Blood flow Bypass Cell Differentiation process Cell Lineage Cell model Cells Coupling Cues Data Defect Development Dialysis procedure Embryo End stage renal failure Endothelial Cells Endothelium Event Exhibits FOXC1 gene Genetic Goals Growth Health Homeostasis Hypertension Hypoxia Impairment In Vitro Invaded Kidney Kidney Failure Laboratories Laminin Metanephric Diverticulum Molecular Mus Muscle satellite cell NTN1 gene Nephrons Organ Organogenesis Pattern Pharmacology Phenotype Proteins Regulation Renal Replacement Therapy Renal Tissue Reporting Role Signal Transduction Smooth Muscle Smooth Muscle Myocytes Stromal Cells Survival Rate System Testing Time Transgenic Mice Trees Vascular Smooth Muscle Vascular remodeling angiogenesis cell type in vitro testing in vivo kidney vascular structure mouse model mutant neogenin nephrogenesis nephron progenitor overexpression postnatal receptor renal artery renal hypoxia stem cells transcription factor

项目摘要

SUMMARY Approximately 500,000 Americans have end-stage renal disease. Although organ function can be supplemented using dialysis, the 10-year survival rate is just over 10%. Ex vivo organogenesis has the potential to meet this demand by providing functional tissue for renal replacement therapy. However to effectively generate functional kidneys in the laboratory, all cell types within the kidney and their functional ontogeny and coupling must be understood. Renal blood vessels are one such component that is critical to the health and homeostasis of the kidney. Building the kidney's intricate arterial network requires synchronized actions of endothelial cells (ECs) and vascular smooth muscle cells (vSMCs) in a sequence that is poorly understood. vSMCs arise in the developing kidney from Foxd1+ nephrogenic stromal cells (NSCs). Ablation of Foxd1 or Foxd1+ cells cause similar defects in renal arteries suggesting Foxd1+ NSC encoded signals may govern renal arteriogenesis. We have found that the secreted laminin-like protein Netrin-1 (Ntn1) is expressed by Foxc1+ NSCs in the embryonic kidney. To date, the role of Ntn1 during kidney development has not been reported. Genetic ablation of Ntn1 from Foxd1+ NSCs (hereafter denoted as Ntn1NSCKO) blocks formation of a perfused renal arterial tree during development. In addition, we find Ntn1NSCKO display an aberrant vSMCs-associated cortical vasculature and increased kidney hypoxia. As development proceeds, Ntn1NSCKO also exhibit reduced ureteric bud (UB) branching, and postnatal Ntn1NSCKO mice display delayed nephrogenesis with ~30% fewer glomeruli. Our preliminary data identifies a critical role for Ntn1 in kidney development, but the mechanism(s) of this regulation is unknown. In this proposal, we address this and ask which receptor is needed for kidney formation: stromal-neogenin1, NPC-Unc5b or endothelial-Unc5b? We hypothesize that NSC-derived Ntn1 cell-autonomously directs vSMC lineage specification via its receptor neogenin1 (Neo1) and the transcription factor Klf4, to instruct renal arterial tree assembly, upon which nephron development indirectly depends. We will test this hypothesis by carrying out following aims: 1) We will test the cell autonomy of NSC-derived Ntn1 signaling during renal arterial assembly, by asking how the stroma responds upon absence of Ntn1, where ectopic SMCs come from in the mutants, and which Ntn1 receptors (hence which cell types) are required for arterial development (which recapitulate the Ntn1 phenotype when ablated). 2) We will examine if aberrant nephrogenesis is caused directly via Ntn1 loss in NPCs, or indirectly due to failure of renal arteriogenesis. We will characterize failed nephrogenesis in the Ntn1 mutant kidneys; we will use in vitro systems to see what cell types respond to Ntn1 (NPCs versus ECs); we will test whether late deletion of Ntn1 recapitulates the Ntn1 mutant phenotype, as it bypasses failed arteriogenesis and associated hypoxia; and lastly we will test the role of hypoxia on NPCs directly. 3) We will examine whether Klf4 is required for stromal differentiation and renal arteriogenesis, and whether it signals downstream of Ntn1.

总结