The role of Hippo signaling in palate development

Hippo 信号在味觉发育中的作用

• 批准号: 10370207
• 负责人: Alice Fitzgerald Goodwin
• 金额: $ 5.4万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10370207
• 关键词: Actins; Affect; Anterior; Antibodies; Apoptosis; Area; Binding; Biological Process; Bromodeoxyuridine; Candidate Disease Gene; Cell Nucleus; Cell Proliferation; Cells; Cellular Morphology; Cellular biology; Cleft Palate; Complex; Cre driver; Cytoskeleton; Data; Defect; Development; Distal; Embryo; Eosine Yellowish; Esthetics; Extracellular Matrix; FOXF1 gene; Failure; Fibronectins; Foundations; Future; Genetic Transcription; Geometry; Goals; Golgi Apparatus; Hard Palate; Human; Immunofluorescence Immunologic; In Situ Hybridization; In Vitro; Individual; Lateral; Lead; Life; Lifting; Link; Live Birth; Maxilla; Measures; Medial; Mesenchymal; Mesenchyme; Molecular; Molecular Mechanisms of Action; Morbidity - disease rate; Morphogenesis; Morphology; Mus; Myosin Type II; Nasal cavity; Nuclear; Operative Surgical Procedures; Oral cavity; Organ; Organ Size; Palate; Pathway interactions; Patients; Phenotype; Positioning Attribute; Preparation; Prevalence; Process; Proteins; Research Proposals; Rho-associated kinase; Role; Secondary Palate; Shapes; Signal Pathway; Signal Transduction; Soft Palate; Specialist; Stains; Stretching; Supine Position; Tenascin; Testing; Therapeutic Intervention; Tissues; Tongue; Transcription Coactivator; Work; blebbistatin; congenital anomaly; density; experimental study; improved; insight; latrunculin A; palatal shelves; palatogenesis; periostin; response; skeletal; therapy outcome; tissue repair; transcriptome sequencing

PROJECT SUMMARY Clefting of the secondary palate is one of the most common congenital anomalies, with a prevalence of 1/1,500 live births. Individuals with cleft palate can be treated by a team of specialists to functional and esthetic norms; however, the current treatment requires multiple surgeries throughout life, which are associated with significant morbidities, and thus, there is an opportunity to improve therapies and outcomes. An increased understanding of the biological processes underlying palatogenesis will provide a foundation on which improved interventions and therapies will be built for patients with cleft palate. Secondary palate development is a complex, multi-step process in which the palatal shelves develop from the maxillary processes and grow vertically, lateral to the developing tongue. The palatal shelves then reorient into a horizontal position dorsal to the tongue in a process termed palatal shelf elevation. The shelves grow horizontally to meet at the midline and fuse to form the hard and soft palate that separate the oral and nasal cavities. The process of palatal shelf elevation is one of the least understood aspects of palatogenesis. Tremendous change in tissue tension and morphology occurs in the palatal shelves during palatal shelf elevation, yet how tension is generated and interpreted by the cells to result in tissue remodeling is not understood. The Hippo pathway is a recently discovered mechanosensory pathway that regulates organ size and tissue repair by controlling proliferation, apoptosis, and differentiation. The downstream targets of the Hippo pathway, Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), translocate to the nucleus and regulate gene transcription in response to change in cell geometry, extracellular matrix (ECM) stiffening, and physical stretching. In order to probe for a link between tension and morphological change in the palatal shelves during elevation, this proposal investigates the Hippo signaling pathway in secondary palate formation. Deletion of Yap and Taz in a subset of secondary palate mesenchymal cells results in cleft palate and, specifically, defects in palatal shelf elevation. This research proposal will determine the role of YAP/TAZ in palatal shelf elevation and test the hypothesis that YAP/TAZ are activated by tension in the palatal shelves, created by ECM and cytoskeleton remodeling, to induce gene transcription required for elevation. Aim 1 will analyze changes in the palatal mesenchyme with deletion of Yap and Taz and determine the role of Hippo signaling in palatogenesis. Aim 2 will establish the molecular mechanism of action of YAP/TAZ in palate development by determining transcriptional targets of YAP/TAZ. This work will bring new insight into the physical and cellular biology underlying palate elevation that will broaden our understanding of palatogenesis and clefting of the secondary palate, guiding future therapies for patients with cleft palate.

项目摘要 次生口感是最常见的先天性异常之一，患病率为1/1,500 活产。 cle裂的个体可以由专家团队对待功能和美学规范。 但是，当前的治疗需要一生多次手术，这与大量有关 病态，因此，有机会改善疗法和结果。越来越多的理解 在palategenation的基础生物过程中，将为改进的干预措施提供基础 和疗法将为口腔裂的患者建造。 次要味觉开发是一个复杂的多步骤过程 上颌过程并垂直生长，向发育中的舌头横向。然后，帕拉特货架重新定位 在称为pale架架子的过程中，舌头向背侧置于舌头的水平位置。货架生长 水平在中线开会并融合，形成分离口头和鼻腔的硬质和柔软的口感 腔。 pal质架子抬高的过程是古质发生的最低知识之一。 帕拉特架子期间的帕拉特架子发生了组织张力和形态的巨大变化 抬高，但是细胞如何产生和解释张力以导致组织重塑 理解。 河马途径是最近发现的机械感觉途径，可调节器官大小和组织 通过控制增殖，凋亡和分化来维修。河马途径的下游目标， 与PDZ结合基序（TAZ）（TAZ）的是相关蛋白（YAP）和转录共激活因子，转运为 细胞核和调节基因转录响应细胞几何形状，细胞外基质（ECM）的变化 僵硬和身体伸展。为了探测张力与形态变化之间的联系 该提案在海拔期间的pa架架子上调查了次要口感的河马信号通路 形成。 在一部分腹膜间充质细胞中删除YAP和TAZ，导致left裂，并且 具体而言，帕拉特架子架的缺陷。该研究建议将决定YAP/TAZ在 帕拉塔尔架子抬高并检验了Yap/taz被palatal架子的张力激活的假设， 由ECM和细胞骨架重塑创建，以诱导升高所需的基因转录。目标1意志 分析具有YAP和TAZ缺失的palatal间充质的变化，并确定河马的作用 在古质发生中的信号传导。 AIM 2将建立YAP/TAZ在pape中的分子作用机理 通过确定YAP/TAZ的转录目标来开发。这项工作将为您带来新的见解 物理和细胞生物学基础味觉抬高，这将扩大我们对古质发生的理解 和次要味觉的裂纹，指导口腔left裂患者的未来疗法。