Trophic interactions directing proper kidney development

营养相互作用指导肾脏的正常发育

• 批准号: 10112900
• 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
• 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/10112900
• 关键词: 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; Lead; Mediating; Mediator of activation protein; 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; Regulation; Renal function; Research; Role; Salivary Glands; Seminal; Shapes; Signal Pathway; Signal Transduction; Signaling Molecule; Three-Dimensional Imaging; Tissues; Transplantation; Work; blood filtration; 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

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调节肾脏的信号因子 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.