Molecular Regulation of Ocular Gland Development

眼腺发育的分子调控

• 批准号: 7659617
• 负责人: VENKATESH GOVINDARAJAN
• 金额: $ 34.83万
• 依托单位: CREIGHTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7659617
• 关键词: Affect; Blindness; Cornea; Corneal Abrasion; Development; Developmental Biology; Differentiation and Growth; Disease; Dominant-Negative Mutation; Dry Eye Syndromes; Edar-associated death domain; Epithelial; Epithelial Cells; Etiology; Eye; FGF10 gene; Family; Fibroblast Growth Factor; Functional disorder; Generations; Gland; Goals; Growth; Harderian Gland; Homologous Gene; Human; Intracellular Second Messenger; Knowledge; Knowledge acquisition; Lacrimal gland structure; Lead; Ligands; Limb structure; Lung; Mediating; Mesenchymal; Modeling; Molecular; Morphogenesis; Mus; Mutant Strains Mice; Mutation; Oral cavity; Organ; Pathogenesis; Patients; Physiology; Pituitary Gland; Prostate; Regulation; Research Personnel; Role; Salivary Glands; Second Messenger Systems; Shapes; Signal Pathway; Signal Transduction; Surface; Syndrome; System; Testing; Thyroid Gland; Transgenic Mice; Tumor Necrosis Factor Receptor; Woman; aging population; alternative treatment; clinically significant; corneal epithelium; ectodysplasin; extracellular; eye dryness; fibroblast growth factor 10; gain of function; gland development; lacrimal; loss of function; member; novel therapeutic intervention; ocular surface; programs; receptor; research study; transcription factor

DESCRIPTION: Dry eye syndrome affects millions of people worldwide and is one of the most common ocular diseases. Dry eye syndromes are relatively common among the aging population and in women. Though the pathogenesis of dry eye likely involves multiple components, lacrimal gland dysfunction and tear deficiencies are major components. The absence of tears, in severe cases, can lead to abrasion of the corneal surface and blindness. Though lacrimal gland physiology has been well studied, relatively very little is known about the regulatory mechanisms that shape lacrimal gland development. Our long-term goal is to define these regulatory mechanisms and to build a comprehensive model of glandular development. Acquisition of this knowledge will be critical for devising alternative treatment options for patients with lacrimal gland disorders such as dry eye syndromes. Our previous studies have shown that FGF-10, a member of the fibroblast growth factor (FGF) family, is both necessary and sufficient for initiation of differentiation of lacrimal and Harderian glands in the murine eye. These studies established FGF-10 as an important component of the signaling system that induces glandular growth and Differentiation. Mutations in FGF-10 in human patients have been shown to be the underlying cause for aplasia of the lacrimal and salivary glands (ALSG) syndrome, a condition characterized by irritable eyes and dryness of the mouth. These findings underscore the importance of FGF-10 signaling to human lacrimal gland development. The objective of this application is to build on our previous studies and define the roles of downstream components of the FGF-10 signaling pathway that are critical for glandular differentiation. We will focus our efforts on Ras, a downstream effector of FGF-10 signaling (Aim 1), Sprouty, a downstream target and antagonist of FGF-10 signaling (Aim 2), and Edar (ectodysplasin receptor), a downstream target of FGF-10 signaling (Aim 3). These studies will be performed by gain- and loss-of-function studies in mice. As the FGF-10 signaling pathway has been shown to be a critical regulator of branching and epithelial-mesenchymal interactions in multiple organ rudiments including the lungs and limbs, a clear understanding of the mechanistic details of the FGF-10 signaling pathway will have broad significance in the field of developmental biology. In addition, the proposed studies will, in the long-term, allow the development of novel therapeutic approaches for treatment of patients with dry eye syndromes.

描述：干眼症综合症会影响全球数百万的人，并且是最常见的眼部疾病之一。干眼综合征在老龄化人群和女性中相对普遍。尽管干眼症的发病机理可能涉及多种成分，但泪腺功能障碍和泪液缺陷是主要成分。在严重的情况下，没有泪水会导致角膜表面和失明。尽管对泪腺生理学进行了充分的研究，但对塑造泪腺发育的调节机制的了解相对较少。我们的长期目标是定义这些调节机制，并建立腺体发育的综合模型。获得这些知识的获取对于为泪腺疾病（如干眼综合征）的患者设计替代治疗方案至关重要。我们先前的研究表明，FGF-10是成纤维细胞生长因子（FGF）家族的成员，对于鼠眼中富集和硬腺腺体的分化是必要且足够的。这些研究将FGF-10确定为诱导腺体生长和分化的信号系统的重要组成部分。人类患者中FGF-10的突变已被证明是富富富集和唾液腺（ALSG）综合征的基本原因，这种疾病的特征是眼睛易怒和口腔干燥。这些发现强调了FGF-10信号传导对人泪腺发育的重要性。该应用的目的是建立我们以前的研究，并定义FGF-10信号通路的下游成分的作用，这对于腺体分化至关重要。我们将重点放在RAS上，RAS是FGF-10信号传导的下游效应器（AIM 1），Sproty，下游目标和FGF-10信号传导的对手（AIM 2）和Edar（Ectodysplasin受体），FGF-10信号的下游目标（AIM 3）。这些研究将通过小鼠的功能丧失研究进行。由于已显示FGF-10信号通路是包括肺部和四肢在内的多个器官方向存在的分支和上皮 - 间质相互作用的关键调节剂，因此对FGF-10信号传导途径的机械细节的清晰理解在发育生物学领域中具有广泛的意义。此外，拟议的研究将长期发展，允许开发新型的治疗方法来治疗干眼症患者。