Trophic interactions directing proper kidney development

摘要 肾功能依赖于与肾神经协调的有组织的血管网络来维持 哺乳动物的动态平衡。尽管它们具有生理意义，但我们对这些网络如何 对肾脏发育的影响极其有限。我们的长期目标是解剖 肾脏发育过程中神经血管网络的形成和功能，并将这些原理应用于 认识和治疗肾脏疾病。我们假设有模式的神经血管网络调节 肾脏通过信号分子的局部释放而发育。我们认为这种干扰是合理的 正常的神经血管形态和功能将对肾脏的发育和生理产生影响。这是 对先天畸形和新生儿急性肾损伤等可能造成扰动的情况具有重要意义 发展神经血管网络，促进疾病进展。为此，我们开创了 努力询问神经血管网络在发育中的小鼠肾脏中的作用。我们发现， 消融神经和破坏神经血管网络的模式会导致肾发育不全 发育不正常。我们预测神经血管细胞释放调节肾脏的信号因子 发展，并确定了候选因素。我们的建议旨在：1)确定神经如何进行调解 肾脏发育；2)探讨神经血管构型在肾脏发育中的作用和意义 3)研究神经血管产生的信号如何促进肾脏发育。我们将利用一个 基因小鼠和人类肾脏器官模型的结合，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开展我们的调查和获得 机械的洞察力。成人肾脏生理学将被分析，以了解发育表型 相互关联并导致功能受损。总之，我们的发现将提供新的见解，并推动我们的 了解建立一个适当的、有功能的肾脏所需的协调细胞功能。当前 晚期肾病患者的治疗选择仅限于透析和移植。显然，这是新的 治疗策略是必要的。能够在体外设计可移植的肾脏或 在体内再生/修复它们将有助于减轻对透析和供体器官的需求 供给。然而，要完成这样的壮举，需要彻底了解肾脏是如何形成的。 在发育过程中，以及推动这一过程的细胞相互作用，包括神经血管 网络。

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.