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Trophic interactions directing proper kidney development

营养相互作用指导肾脏的正常发育

基本信息

批准号：
10540685
负责人：
Lori L O'Brien
金额：
$ 33.61万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
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：
2020-02-21 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10540685
关键词：
Ablation Acute Renal Failure with Renal Papillary Necrosis Address Adult Affect Age Attention Blood Pressure Blood Vessels Blood flow Cell physiology Cells Chemical Sympathectomy Chemicals Chronic Kidney Failure Congenital Abnormality Cues Denervation Development Dialysis procedure Differentiation and Growth Disease Disease Progression Embryo Endothelial Cells Engineering Familial Dysautonomia Genetic Goals Health Heart Homeostasis Hormone secretion Human Imaging Techniques Injury to Kidney Investigation Kidney Kidney Diseases Kidney Transplantation Knock-out Knowledge Mediating Mediator Methodology Modeling Modernization Mus NTN1 gene Natural regeneration Neonatal Nerve Neurodevelopmental Disorder Newborn Infant Organ Organ Donor Organoids Pancreas Paracrine Communication Pathway interactions Patients Pattern Phenotype Physiological Physiology Play Process Rationalization Regulation Renal function Research Role Salivary Glands Seminal Shapes Signal Pathway Signal Transduction Signaling Molecule Three-Dimensional Imaging Tissues Transplantation Work blood filtration candidate identification congenital anomaly fetal in vivo induced pluripotent stem cell insight mouse model mutant nephrogenesis nerve supply netrin-3 neural network neurovascular new therapeutic target novel novel therapeutic intervention organ growth prevent regenerative therapy release factor repaired virtual

项目摘要

Abstract Renal function is dependent on an organized vascular network which coordinates with renal nerves to maintain mammalian homeostasis. Despite their physiological significance, our understanding of how these networks are established and influence kidney development are extremely limited. Our long-term goal is to dissect neurovascular network formation and function during kidney development and apply these principles to understanding and treating kidney disease. We hypothesize that patterned neurovascular networks modulate kidney development through the localized release of signaling molecules. We rationalize that disruptions to normal neurovascular form and function will have implications for kidney development and physiology. This is significant to conditions such as congenital anomalies and neonatal acute kidney injury which could perturbate developing neurovascular networks and contribute to disease progression. To this end, we have pioneered efforts to interrogate the role of neurovascular networks in the developing mouse kidney. We have found that ablating nerves and disrupting the patterning of neurovascular networks results in hypoplastic kidneys with abnormal development. We predict that neurovascular cells release signaling factors that regulate kidney development and have identified candidate factors. Our proposal aims to: 1) determine how nerves mediate kidney development; 2) interrogate the role of neurovascular patterning in kidney development and implications for function; 3) investigate how neurovascular produced signals promote kidney development. We will utilize a combination of genetic mouse and human kidney organoid models, state-of-the-art imaging techniques, quantitative analyses, and various modern and novel methodologies to carry out our investigations and gain mechanistic insights. Adult renal physiology will be analyzed to understand how developmental phenotypes correlate and lead to compromised function. Together, our findings will provide novel insights and advance our understanding of the coordinated cellular functions required to establish a proper, functional kidney. Current treatment options for patients with advanced kidney disease are limited to dialysis and transplant. Clearly, new therapeutic strategies are necessary. Being able to engineer transplantable kidneys ex vivo or regenerate/repair them in vivo would help alleviate the need for dialysis and donor organs which are in short supply. However, to accomplish such feats requires a thorough understanding of how kidneys are formed during development, and the cellular interactions which drive this process which includes neurovascular networks.

摘要肾功能依赖于有组织的血管网络，该血管网络与肾神经协调以维持哺乳动物体内平衡尽管它们在生理上很重要，但我们对这些网络的理解对肾脏发育的影响极其有限。我们的长期目标是解剖神经血管网络的形成和功能在肾脏发育过程中，并应用这些原则，了解和治疗肾脏疾病。我们假设，模式化的神经血管网络调节通过局部释放信号分子促进肾脏发育。我们合理解释了正常的神经血管形式和功能将对肾脏发育和生理学产生影响。这是对于先天性异常和新生儿急性肾损伤等可能干扰发展神经血管网络并促进疾病进展。为此，我们开创了研究神经血管网络在小鼠肾脏发育中的作用。我们发现消融神经和破坏神经血管网络的模式导致发育不全的肾脏，异常发育我们预测，神经血管细胞释放信号因子，发展并确定候选因素。我们的建议旨在：1）确定神经如何介导肾脏发育; 2）询问神经血管模式在肾脏发育中的作用及其意义 3）研究神经血管产生的信号如何促进肾脏发育。我们将利用遗传小鼠和人类肾脏类器官模型的组合，最先进的成像技术，定量分析，以及各种现代和新颖的方法来进行我们的调查，机械的洞察力。将分析成人肾脏生理学，以了解发育表型导致功能受损总之，我们的研究结果将提供新的见解，并推动我们的了解建立一个适当的、功能性的肾脏所需的协调细胞功能。电流晚期肾病患者的治疗选择仅限于透析和移植。显然，新治疗策略是必要的。能够体外设计可移植的肾脏，在体内再生/修复它们将有助于减轻对透析和捐赠器官的需求，供应然而，要完成这样的壮举，需要彻底了解肾脏是如何形成的以及驱动这一过程的细胞相互作用，包括神经血管网络.