MECHANICS OF EARLY BRAIN AND EYE DEVELOPMENT

早期大脑和眼睛发育的机制

• 批准号: 7946286
• 负责人: LARRY A TABER
• 金额: $ 29.84万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7946286
• 关键词: Actins; Anencephaly; Autistic Disorder; Brain; Cell physiology; Cephalic; Cerebrospinal Fluid Pressure; Characteristics; Coloboma; Computer Simulation; Development; Distal; Drug Exposure; Embryo; Engineering; Eye; Eye Development; F-Actin; Feedback; Figs - dietary; Genes; Genetic; Growth; Human; Hydrocephalus; Knock-out; Laboratories; Measurement; Measures; Mechanics; Microdissection; Microphthalmos; Midbrain structure; Modeling; Molecular Genetics; Morphogenesis; Mus; Neural tube; Optic vesicle; Optical Coherence Tomography; Organ; Pattern; Plant Roots; Play; Pregnancy; Prevention; Primary Brain Vesicle; Process; Property; Prosencephalon; Research; Resolution; Retina; Role; Schizophrenia; Shapes; Solid; Specific qualifier value; Stress; Structure; Time; Tissues; Vesicle; Visual impairment; Work; base; eye formation; fluorescence imaging; hindbrain; insight; lens; nervous system disorder; optic cup; prospective; public health relevance; relating to nervous system; research study; response; theories

DESCRIPTION (provided by applicant): In human embryos, the primary subdivisions of the brain (forebrain, midbrain, and hindbrain) are formed by the fourth week of gestation. During this time, the primitive eyes (optic vesicles) emerge as protrusions from the forebrain. The forms of these organs are highly conserved. Abnormalities in size and shape of the early brain are known to cause serious neurological disorders such as anencephaly, hydrocephalus, autism, and schizophrenia, while improper eye morphogenesis can cause coloboma and microphthalmia, leading to severe visual impairment. Prevention and treatment of these maladies requires understanding of their root cause. While much is now known about the molecular and genetic factors that regulate brain and eye development, the mechanical processes that actually create these structures remain poorly understood. The main objective of this proposed research is to determine the morphogenetic mechanisms that shape the early embryonic brain and eye. The specific aims are the following: (1) Determine the mechanisms that drive growth and morphogenesis of the developing brain vesicles. (2) Determine the mechanisms that drive growth and morphogenesis of the optic vesicle before the optic cup forms. (3) Determine the mechanisms that drive invagination and shaping of the optic cup. To accomplish these aims, we will integrate computational modeling with quantitative experimental measurements. The models are based on fundamental engineering theories of nonlinear solid mechanics. The experiments, to be conducted on chick and mouse embryos, will employ high-resolution optical coherence tomography (OCT) and fluorescence imaging to measure changes in global and local geometry (e.g., curvature and wall strains) and microstructure (e.g., actin distribution), microdissection to determine and perturb tissue stress, drug exposure and genetic knockouts to perturb cellular function, and measurements of embryonic cerebrospinal fluid pressure and regional mechanical properties. This project will provide important new insights into the morphogenetic mechanisms of brain and eye development. PUBLIC HEALTH RELEVANCE: Abnormalities in size and shape of the early brain are known to cause serious neurological disorders such as anencephaly, hydrocephalus, autism, and schizophrenia, while improper eye development can cause visual impairment. Prevention and treatment of these maladies requires understanding their root cause. This project will provide important new understanding of the morphogenetic mechanisms that create the embryonic brain and eye.

描述（由申请人提供）：在人类胚胎中，大脑的主要部分（前脑、中脑和后脑）在妊娠第四周形成。在此期间，原始眼睛（视神经泡）从前脑突出。这些器官的形式高度保守。众所周知，早期大脑的大小和形状异常会导致严重的神经系统疾病，例如无脑畸形、脑积水、自闭症和精神分裂症，而眼睛形态发生不当会导致缺损和小眼畸形，从而导致严重的视力障碍。预防和治疗这些疾病需要了解其根本原因。虽然现在人们对调节大脑和眼睛发育的分子和遗传因素了解很多，但实际上创建这些结构的机械过程仍然知之甚少。这项研究的主要目的是确定塑造早期胚胎大脑和眼睛的形态发生机制。具体目标如下：（1）确定驱动发育中的脑囊泡生长和形态发生的机制。 (2) 确定视杯形成前驱动视泡生长和形态发生的机制。 (3) 确定驱动视杯内陷和成形的机制。为了实现这些目标，我们将把计算模型与定量实验测量相结合。这些模型基于非线性固体力学的基础工程理论。这些实验将在小鸡和小鼠胚胎上进行，将采用高分辨率光学相干断层扫描（OCT）和荧光成像来测量整体和局部几何形状（例如曲率和壁应变）和微观结构（例如肌动蛋白分布）的变化，显微解剖以确定和扰乱组织应力，药物暴露和基因敲除扰乱细胞功能，以及胚胎脑脊液压力和区域机械特性的测量。该项目将为大脑和眼睛发育的形态发生机制提供重要的新见解。 公众健康相关性：众所周知，早期大脑大小和形状的异常会导致严重的神经系统疾病，例如无脑畸形、脑积水、自闭症和精神分裂症，而眼睛发育不当会导致视力障碍。预防和治疗这些疾病需要了解其根本原因。该项目将为创造胚胎大脑和眼睛的形态发生机制提供重要的新认识。