Regulation of Zebrasfish Development by Semaphorin-Olfactomedin 2 Interactions

Semaphorin-Olfactomedin 2 相互作用对斑马鱼发育的调节

基本信息

批准号：
7499310
负责人：
Ju-Ahng Lee
金额：
$ 10.43万
依托单位：
NORTH CAROLINA CENTRAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7499310
关键词：
Adult Affect Affinity Area Binding Biological Markers Blood Vessels Cartilage Central Artery Cephalic Cerebrum Complex Congenital Abnormality Defect Development Developmental Process Endothelial Cells Epitopes Event Fishes Gel Genes Glycoproteins Health Benefit Human Immune In Situ Hybridization Injection of therapeutic agent Laboratories Light Link Malignant Neoplasms Nerve Regeneration Nervous system structure Neural Crest Neural Crest Cell Neuropilin-2 Neuropilins Pathology Pathway interactions Personal Satisfaction Phenotype Process Protein Family Proteins Publishing RNA Caps Regulation Resolution Role Semaphorin-3A Semaphorins Signal Pathway Signaling Molecule Staging Structure Testing Transgenic Organisms Tumor Angiogenesis Vascular Endothelial Growth Factors Zebrafish angiogenesis antibody conjugate axon guidance cell motility cerebral vein combinatorial craniofacial early onset extracellular insight interest islet malformation member microangiography migration nervous system development novel olfactomedin pleiotropism plexin protein function protein protein interaction receptor receptor binding research study vasculogenesis

项目摘要

DESCRIPTION (provided by applicant): Semaphorin pathways have been well characterized for their roles in axon guidance. Moreover, recent findings highlight significant roles of this pathway in other critical areas such as vasculogenesis, angiogenesis, cell migration/differentiation, immune regulation, and cancer pathology. The Pi's laboratory has recently identified zebra fish olfactomedin 2 (OM2), a secreted glycoprotein with a highly conserved olfactomedin domain. Initial expression and functional characterization studies revealed OM2's roles in three important developmental processes: axon guidance, neural crest migration/differentiation, and angiogenesis. Analyses on phenotypes of OM2 morphants in comparison with published phenotypes from disrupted semaphorin pathways, consistently led the PI to formulate the following overall hypothesis: OM2 regulates axon guidance, neural crest cell migration/differentiation, and angiogenesis via its interaction with the semaphorin pathway. In order to test the OM2-semaphorin pathway link in these processes, three Specific Aims are proposed. Specific Aim 1: To test the hypothesis that highly specific cranial axon guidance defects in OM2 morphants are due to the perturbation of direct interaction between OM2 and semaphorin receptor complexes. Specific Aim 2: To test the hypothesis that the absence of pharyngeal cartilages in OM2 morphants is due to the perturbation of cranial neural crest cell (cNCC) migration and/or differentiation, which is critically dependent upon semaphorin pathways. Specific Aim 3: To test the hypothesis that highly specific defects found only in late-onset cranial vasculature in OM2 morphants are due to perturbation in semaphorin-neuropilin and/or VEGF-neuropilin pathways. These hypotheses will be tested by (1) high resolution expression analysis of OM2 and semaphorin signaling molecules, deficiency of which results in highly similar phenotypes as OM2-deficiency phenotypes; (2) concomitant inhibition of semaphorin components and OM2 to verify functional convergence of OM2 in the semaphorin signaling pathway; (3) testing direct molecular interactions between OM2 and components of the semaphorin receptor complex. Given that the semaphorin pathway is known to be critically involved in adult nerve regeneration, craniofacial malformation (most frequent human birth defects), and tumor angiogenesis, novel insights into the regulation of this signaling pathway will be of paramount health benefit.

描述（由申请人提供）：信号蛋白通路在轴突引导中的作用已被充分表征。此外，最近的研究结果强调了该途径在其他关键领域的重要作用，如血管生成、血管生成、细胞迁移/分化、免疫调节和癌症病理学。 Pi 的实验室最近鉴定出斑马鱼 olfactomedin 2 (OM2)，这是一种具有高度保守的 olfactomedin 结构域的分泌糖蛋白。初步表达和功能表征研究揭示了 OM2 在三个重要发育过程中的作用：轴突引导、神经嵴迁移/分化和血管生成。对 OM2 突变体表型的分析，与已发表的信号蛋白通路中断的表型进行比较，一致导致 PI 制定以下总体假设：OM2 通过与信号蛋白通路的相互作用来调节轴突引导、神经嵴细胞迁移/分化和血管生成。为了测试这些过程中的 OM2-信号蛋白通路链接，提出了三个具体目标。具体目标 1：检验以下假设：OM2 变形体中高度特异性的颅轴突引导缺陷是由于 OM2 和信号蛋白受体复合物之间的直接相互作用的扰动造成的。具体目标 2：检验以下假设：OM2 变形体中咽软骨的缺失是由于颅神经嵴细胞 (cNCC) 迁移和/或分化的扰动造成的，这严重依赖于信号蛋白通路。具体目标 3：检验以下假设：仅在 OM2 突变体的迟发性颅血管系统中发现的高度特异性缺陷是由于信号蛋白-神经毡蛋白和/或 VEGF-神经毡蛋白途径的扰动所致。这些假设将通过（1）OM2和信号蛋白信号分子的高分辨率表达分析来检验，其缺陷导致与OM2缺陷表型高度相似的表型； (2)同时抑制semaphorin成分和OM2，验证OM2在semaphorin信号通路中的功能收敛； (3) 测试 OM2 和信号蛋白受体复合物成分之间的直接分子相互作用。鉴于已知信号蛋白通路与成人神经再生、颅面畸形（最常见的人类出生缺陷）和肿瘤血管生成密切相关，因此对该信号通路调节的新见解将具有最重要的健康益处。