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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：
10312135
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/10312135
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

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