Cytoneme-mediated hedgehog signaling in cardiac development

心脏发育中细胞因子介导的刺猬信号

基本信息

批准号：
9760368
负责人：
Brent Malcolm Wood
金额：
$ 6.12万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9760368
关键词：
3-Dimensional Actins Adult Agonist Architecture Calcium Cardiac Cardiac development Cells Cellular Structures Characteristics Clinical Trials Congenital Heart Defects Coronary Coupling Development Disease Dorsal Drosophila genus Ectoderm Electron Microscopy Embryo Endocytic Vesicle Erinaceidae Etiology Filopodia Future Gene Expression Gene Expression Profile Glutamates Goals Heart Individual Intracellular Membranes Label Light Mediating Membrane Mesoderm Mesoderm Cell Morphology Muscle Cells Myocardial Infarction Myocardium Neurons Organ Paracrine Communication Pathway interactions Pattern Pharmacology Process Regenerative Medicine Resolution Safety Side Signal Transduction Specificity Structure Synapses System Target Populations Testing Thinness Tissues Travel Tube Wing Work angiogenesis base cell type confocal imaging coronary vasculature exosome extracellular hedgehog signal transduction imaginal disc insight light microscopy microscopic imaging morphogens preservation regenerative small molecule smoothened signaling pathway therapeutic target

3-Dimensional Actins Adult Agonist Architecture Calcium Cardiac Cardiac development Cells Cellular Structures Characteristics Clinical Trials Congenital Heart Defects Coronary Coupling Development Disease Dorsal Drosophila genus Ectoderm Electron Microscopy Embryo Endocytic Vesicle Erinaceidae Etiology Filopodia Future Gene Expression Gene Expression Profile Glutamates Goals Heart Individual Intracellular Membranes Label Light Mediating Membrane Mesoderm Mesoderm Cell Morphology Muscle Cells Myocardial Infarction Myocardium Neurons Organ Paracrine Communication Pathway interactions Pattern Pharmacology Process Regenerative Medicine Resolution Safety Side Signal Transduction Specificity Structure Synapses System Target Populations Testing Thinness Tissues Travel Tube Wing Work angiogenesis base cell type confocal imaging coronary vasculature exosome extracellular hedgehog signal transduction imaginal disc insight light microscopy microscopic imaging morphogens preservation regenerative small molecule smoothened signaling pathway therapeutic target

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项目摘要

Project Summary / Abstract Hedgehog (Hh) signaling is a critical initiator of developmental patterning in many tissues and organs including the heart. Beyond development, Hh signaling acts to promote angiogenesis and epicardial regenerative capacity, preserve function after myocardial infarction, and maintain coronary vasculature in adult myocardium. Cardiac development requires trans-tissue Hedgehog signaling that is specifically received by a subset of cardiac mesodermal cells. This study will test whether Hedgehog is transported by specialized signaling filopodia known as cytonemes from the embryonic ectoderm to its target cells. Cytonemes are thin actin-based filopodia which connect paracrine signal producing cells to receiving cells. Cytonemes have been shown to be the mechanism by which morphogens are dispersed in many other developmental systems but have never been specifically examined in cardiac development. We hypothesize that cytonemes extending between the dorsal ectoderm and cardioblasts are responsible for the specificity of Hh distribution. The presence, function and necessity of Hh- carrying cytonemes for cardiac tube development will be assessed using live confocal imaging of embryos which express fluorescently tagged CD4 and Hh in the Drosophila embryonic ectoderm, mesoderm, or cardioblasts. To further examine how cytonemes distribute Hh, electron microscopy (EM) will be used in the Drosophila larval imaginal wing disc, where cytonemes have been well-established. Because cytonemes share some characteristics of neurons, we will test whether a bouton structure is found at the junction between cytonemes and their target cells. EM imaging will also be used to answer whether cytonemes connect to multiple or single cells, and how Hh is transported along the cytonemes (e.g. membrane associated exosomes, intracellular membrane, endocytic vesicles). Identification of cytoneme-mediated Hh delivery during cardiac development would expand the way in which we understand and potentially target congenital heart defects, and influence future approaches in regenerative medicine.

项目摘要 /摘要刺猬（HH）信号是在包括心。除了发育之外，HH信号传导还可以促进血管生成和心外膜再生能力，在心肌梗死后保留功能，并维持成年心肌的冠状动脉血管。心脏开发需要一部分心脏的跨组织刺猬信号传导中胚层细胞。这项研究将测试刺猬是否通过已知的专门信号传导运输作为从胚胎外胚层到其靶细胞的细胞。细胞是基于肌动蛋白的薄丝状菌素将产生细胞的旁分泌信号连接到接收细胞。细胞质已被证明是机制通过哪些其他发展系统将形态剂分散，但从未有过专门在心脏发展中进行了检查。我们假设在背外胚层和心脏细胞负责HH分布的特异性。 HH-的存在，功能和必要性将使用胚胎的实时共焦成像来评估用于心脏管发育的细胞质在果蝇胚胎外胚层，中胚层或心脏细胞中表达荧光标记的CD4和HH。为了进一步检查细胞质如何分布HH，将在果蝇幼虫中使用电子显微镜（EM）想象中的机翼圆盘，在该圆盘上已经建立了良好的。因为细胞分享一些神经元的特征，我们将测试在细胞之间的连接处是否发现了胸子结构及其目标细胞。 EM成像也将用于回答细胞是否连接到多个或单一连接细胞，以及HH沿细胞的运输方式（例如膜相关外泌体，细胞内膜，内吞囊泡）。鉴定心脏发育过程中的胞素介导的HH递送将扩大我们理解并可能针对先天性心脏缺陷的方式，并影响再生医学的未来方法。