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Understanding trigeminal ganglion development through the lens of Familial Dysautonomia

从家族性自主神经功能障碍的角度了解三叉神经节的发育

基本信息

批准号：
10584608
负责人：
LISA A TANEYHILL
金额：
$ 7.73万
依托单位：
UNIV OF MARYLAND, COLLEGE PARK
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10584608
关键词：
Address Affect Afferent Neurons Affinity Affinity Chromatography Anatomy Animal Model Apoptotic Binding Biochemistry Biological Assay Biological Models Brain Cartilage Cell Differentiation process Cells Cephalic Chick Chick Embryo Chick model Congenital Abnormality Cranial Nerves Craniofacial Abnormalities Cytoplasm Data Data Set Defect Development Disease Disparate Distal Embryo Embryology Embryonic Development Ensure Epithelium Esthesia Etiology Evaluation Exhibits Face Facial Pain Familial Dysautonomia Functional disorder Ganglia Genes Global Change Goals Head Head and neck structure Health Hour Human Human Development Human body Impairment Individual Knowledge Ligands Mass Spectrum Analysis Mediating Mesenchyme Microscopy Mission Modeling Molecular Morphology Mus Mutation National Institute of Child Health and Human Development Nerve Neural Crest Neural Crest Cell Neurons Nociceptors Pain Pathway interactions Pattern Perception Peripheral Nervous System Phenotype Population Positioning Attribute Process Proteins Proteome Proteomics Public Health Quality of life Regulation Research Role Sensory Signal Transduction Skin Pigmentation Structure of trigeminal ganglion Sympathetic Ganglia Temperature Temperature Sense Testing Therapeutic Time Tissues United States National Institutes of Health Work afferent nerve autonomic nerve bone candidate identification candidate validation cell type design embryo cell experimental study human disease improved in vivo innovation insight interdisciplinary approach lens loss of function mouse model nerve supply novel protein complex protein function protein transport receptor somatosensory tool trafficking

项目摘要

PROJECT SUMMARY Cranial neural crest cells (NCCs) and placode cells (PCs) differentiate to form diverse cell types, including sensory neurons, cartilage and bone, and skin pigment cells. Abnormalities that occur during NCC and PC development are thus directly responsible for many human diseases, including Familial Dysautonomia (FD), a sensory and autonomic nerve disorder characterized, in part, by cranial trigeminal ganglion (TG) dysfunction. Both NCCs and PCs must coalesce together to assemble the TG, which relays somatosensory information from the head to the brain. The dual cellular origin of the TG evokes questions regarding how two distinct cell populations interact to form a single tissue, which constitutes a significant gap in knowledge. In this proposal, we will investigate molecular mechanisms underlying TG development through pioneering studies in both mouse and chick model systems. Our preliminary data demonstrated progressive morphological deficits in the TG and its nerves in a mouse model of FD in which the causative gene, Elongator Complex Protein 1 (Elp1), is deleted in NCCs and their derivatives (Elp1 CKO). Moreover, specific TG neuron subpopulations that sense pain and temperature (nociceptors) are depleted in Elp1 CKO embryos, providing a cellular basis for the phenotypes observed in FD. Altogether, these findings reveal a critical role for Elp1 in TG development; however, the molecular mechanisms by which Elp1 orchestrates the proper establishment of the TG remain largely unknown. Since Elp1 possesses diverse, context-dependent functions, unbiased approaches are required to examine the role of Elp1 exclusively in the TG. To this end, we will use mass spectrometry (MS) at distinct developmental stages to address our working model that Elp1 mediates downstream signaling required for proper formation of the TG and its nerves. The Specific Aims of this application are to: 1) determine the effects of NCC Elp1 loss on the TG proteome and 2) define cell-type specific Elp1-interacting proteins in the TG. In Aim 1, we will delineate the TG proteome in Elp1 CKO vs. littermate controls, identifying candidates whose expression is affected by Elp1 loss. Candidate function will be evaluated in the mouse and chick, with the latter possible due to conservation of Elp1 expression, providing the ability to rapidly perform functional experiments. In Aim 2, we will use affinity-based MS to uncover Elp1 binding partners in the TG specific to PCs (revealed in the Elp1 CKO) and NCC derivatives (identified in controls after comparison to Elp1 CKO), with candidate evaluation proceeding as in Aim 1. The proposed research is innovative because it combines the power of two complementary developmental models (mouse and chick) with a multidisciplinary approach involving embryology, biochemistry, proteomics, and novel microscopy and perturbation assays. These results will significantly advance our knowledge of the molecular mechanisms underscoring intercellular interactions required for the formation and function of not only the TG but also other multicellular tissues, and will shed light on the etiology of diseases like FD and others caused by aberrant NCCs and PCs during embryonic development.

项目摘要颅神经嵴细胞（NCCs）和基板细胞（PC）分化形成不同的细胞类型，包括感觉神经元、软骨和骨以及皮肤色素细胞。NCC和PC期间发生的异常因此，发育直接导致许多人类疾病，包括家族性自主神经功能障碍（FD），感觉和自主神经障碍，部分特征为颅三叉神经节（TG）功能障碍。 NCC和PC必须结合在一起组装TG，TG将体感信息从头部到大脑。TG的双重细胞起源引发了关于两种不同细胞如何人口相互作用形成单一组织，这构成了知识上的重大差距。在这项提案中，我们将通过在小鼠和小鼠中的开创性研究，和小鸡模型系统。我们的初步数据表明，在TG进行性形态缺陷，其神经在FD小鼠模型中，其中致病基因，延长体复合蛋白1（Elp 1），被删除在净捐助国及其衍生物中（Elp 1 CKO）。此外，特定的TG神经元亚群，感觉疼痛，在Elp 1 CKO胚胎中，温度（伤害感受器）被耗尽，为表型提供了细胞基础在FD中观察。总之，这些发现揭示了Elp 1在TG发展中的关键作用;然而， Elp 1协调TG的正确建立的分子机制在很大程度上仍然未知。由于Elp 1具有不同的，依赖于上下文的功能，需要无偏的方法来检查 Elp 1仅在TG中发挥作用。为此，我们将在不同的发展阶段使用质谱法（MS）阶段，以解决我们的工作模型，Elp 1介导的下游信号所需的适当形成， TG和它的神经本申请的具体目的是：1）确定NCC Elp 1损失对 TG蛋白质组和2）定义TG中的细胞类型特异性Elp 1相互作用蛋白。在目标1中，我们将描绘 Elp 1 CKO与同窝对照中的TG蛋白质组，鉴定其表达受 Elp 1丢失。将在小鼠和小鸡中评价候选功能，后者可能是由于保护Elp 1表达，提供快速进行功能实验的能力。在目标2中，我们将使用基于亲和力的MS来揭示PC特异性TG中的Elp 1结合伴侣（在Elp 1 CKO中揭示）， NCC衍生物（与Elp 1 CKO比较后在对照中鉴定），候选评价进行如下目标1。这项研究是创新的，因为它结合了两种互补的力量。发育模型（小鼠和鸡）与多学科的方法，涉及胚胎学，生物化学，蛋白质组学，以及新的显微镜和微扰分析。这些结果将大大促进我们的分子机制的知识，强调细胞间的相互作用所需的形成和不仅TG的功能，而且其他多细胞组织，并将阐明疾病的病因，如 FD和其他由胚胎发育过程中异常的NCC和PC引起的疾病。