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Forebrain angiogenesis in Foxc1 mutant mice

Foxc1突变小鼠的前脑血管生成

基本信息

批准号：
8068348
负责人：
Julie Siegenthaler
金额：
$ 7.87万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8068348
关键词：
Ablation Acute Address Adult Affect Alcohols Anatomy Area Automobile Driving Back Behavior Biochemical Biomedical Research Blood Vessels Blood capillaries Brain Caliber Cell Communication Cell Culture Techniques Cell Differentiation process Cell Maturation Cell Proliferation Cell Separation Cell physiology Cells Cerebral cortex Cerebrum Cessation of life Chronic Phase Core Facility Cues Data Defect Desmin Development Development Plans Differentiation Antigens Dissection Dorsal Elements Embryo Endothelial Cells Environment Enzymes Equipment Etiology Evaluation Experimental Designs Faculty Fetal Alcohol Syndrome Fetal Development Fishes Floor Forebrain Development Gene Dosage Generations Genes Goals Health Hybrids Incubators Individual Institutes Institution Journals Knowledge Ligands Light Medical Meningeal Meninges Mentors Mentorship Microscope Mission Mitotic Molecular Mutant Strains Mice Neocortex Neural Crest Neurons Neurosciences PDGFRB gene Pathway interactions Patient Care Patient Education Perfusion Pericytes Phase Phenotype Point Mutation Preparation Production Prosencephalon Publications Publishing Research Role Severities Signal Pathway Signal Transduction Smooth Muscle Myocytes Spinal Cord Stroke Structure System Techniques Testing Time Tissues Training Tretinoin Tube Universities Vascularization Work angiogenesis animal facility base capillary career career development cell growth cell type college design disability follow-up graduate student hindbrain improved insight interest malformation meetings member mutant neocortical perineural pleasure post-doctoral training programs public health relevance relating to nervous system research facility research study skills stroke recovery tissue culture transcription factor vasculogenesis

项目摘要

DESCRIPTION (provided by applicant): Dr. Julie Siegenthaler's initial interest in neuroscience started at Mount Holyoke College where she majored in the newly formed Neuroscience and Behavior program and was first introduced to experimental design and research while studying behavior in fish for her senior thesis project. After graduating cum laude with high honors in 2000, Dr. Siegenthaler pursued her interests in cellular and molecular neuroscience as a graduate student with Dr. Michael Miller at SUNY Upstate Medical University. While a graduate student, Dr. Siegenthaler described a role for TGF2 in neocortical development and as a potential target of alcohol in the brain defects seen in fetal alcohol syndrome. She continued in Dr. Miller's lab for a brief but productive postdoctoral training where she found that the transcription factor Foxg1 was an important regulator of TGF2 signaling in forebrain development. In total, Dr. Siegenthaler published five 1st author publications while at SUNY Upstate in such journals as Cerebral Cortex and Journal of Neuroscience. In May 2006, Dr. Siegenthaler joined Dr. Sam Pleasure's lab at UCSF where she began work on a project looking at the role of the secreted factors from the meninges in the development of the neocortex. Using Foxc1 mutant mice that fail to make complete meninges and have severe defects in forebrain development, she showed that meningeal-derived retinoic acid is key element driving neuron generation during corticogenesis. This research resulted in a first-author publication in the journal Cell. Dr. Siegenthaler has also generated substantial data regarded the brain vascular defects in the Foxc1 mutants and she is dedicated to developing an independent research plan focused on understanding how different structures and cell types contribute to the formation of the cerebral vasculature. Dr. Siegenthaler has developed a comprehensive career development plan to meet her career goals. While in the mentored K99 phase, Dr. Siegenthaler will continue to benefit from the mentorship and guidance of her sponsor, Dr. Sam Pleasure, and acquire new skills as she completes the specific aims outlined the Research Plan. The experimental data and techniques acquired during the K99 phase will be valuable in the research planned for the R00 phase. Dr. Siegenthaler's long-term goal is to develop a comprehensive, multi-faceted research program that investigates the development and function of the meninges in the embryo and adult, the functional role of Foxc1 in perivascular cells, and the interaction between the neural tissues and the vasculature during brain development. Environment. Dr. Siegenthaler has her own work space and desk on the 5th floor of Rock Hall on the Mission Bay Campus of UCSF. She has full access to the equipment and space of her mentor, Dr. Pleasure, including general lab equipment, centrifuges, freezers, a dissection room and adjacent tissue culture hood and incubators, microscopes, and space in the animal facility. She also has access to UCSF core facilities including those for cell sorting and real time PCR equipment. Dr. Siegenthaler has the equipment and facilities needed to complete the experiments outlined for the K99 phase. Her research will be conducted at UCSF, an extremely well-regarded research institution dedicated to improving the health of individuals through biomedical research, patient care and education. The research facilities at the Mission Bay Campus are part of a substantial effort by UCSF to improve and expand its research capabilities. Along with the neighboring Gladstone Institute, the Mission Bay Campus provides ample opportunities for Dr. Siegenthaler to attend seminars, presentations, journal clubs, and have informal meetings with faculty members that will contribute greatly to her training and preparation for an independent research career. Research. This proposal uses the Foxc1 mutant mice, which have defects in vascular and brain development, to gain further insight into how the brain vasculature forms. Experiments in the K99 phase are designed to understand how the absence of the meninges and defects in forebrain development in the Foxc1 mutants differentially contributes to the blood vessel malformations. Experiments in the R00 phase will investigate potential targets of meningeal-derived signals on endothelial cells, the cell autonomous role for Foxc1 in the differentiation and function of mural cells associated with the vasculature in and around the brain, and further explore the role of the neural-derived signals in the vascularization of the developing cortex. Foxc1 is expressed by neural crest-derived meningeal cells and mural cells (collective term for pericytes and smooth muscle cells) in the developing embryo and in the adult. Yet Foxc1 mutant mice have severe defects in both cortical development and formation of the forebrain vasculature. I have previously shown that the defects in dorsal forebrain development are due to loss of meningeal-derived retinoic acid. My preliminary evidence suggests that retinoic acid from the meninges also regulates endothelial cell proliferation and vessel formation around the forebrain (referred to as the perineural vascular plexus (PNVP). Experiments in specific aim 1 will specifically address the role of retinoic acid in the formation of the PNVP. In specific aim 2, I will address the role of Foxc1 in the differentiation and function of CNS mural cells using mural cell-specific ablation of Foxc1. In addition to defects in the PNVP, the intracortical vasculature fails to form properly in the Foxc1 mutants. In the third aim, I will test the hypothesis that the intracortical vascular phenotype in the Foxc1 mutants is due to loss of important angiogenic cues from the dorsal forebrain. PUBLIC HEALTH RELEVANCE: Stroke is a significant cause of long-term disability and death and can result from congenital vascular defects that occur during fetal development. The research in this proposal seeks to significantly expand our understanding of what controls the formation of the vasculature in and around the cerebral cortex. Understanding how the cerebral vasculature forms will not only shed light on the etiology of congenital vascular malformations but also provide additional insight into the developmental angiogenic pathways that are likely reactivated during stroke recovery.

描述（由申请人提供）：Julie Siegenthaler 博士最初对神经科学的兴趣始于 Mount Holyoke 学院，在那里她主修新成立的神经科学和行为项目，并在为她的高级论文项目研究鱼类行为时首次接触到实验设计和研究。 2000 年以优异成绩毕业后，Siegenthaler 博士在纽约州立大学上州医科大学跟随 Michael Miller 博士攻读研究生，继续追求自己对细胞和分子神经科学的兴趣。在还是一名研究生时，Siegenthaler 博士描述了 TGF2 在新皮质发育中的作用，以及作为酒精在胎儿酒精综合症中所见的大脑缺陷中的潜在目标。她继续在 Miller 博士的实验室进行短暂但富有成效的博士后培训，在那里她发现转录因子 Foxg1 是前脑发育中 TGF2 信号传导的重要调节因子。西根塔勒博士在纽约州立大学北部分校期间总共在《Cerebral Cortex》和《Journal of Neuroscience》等期刊上发表了五篇第一作者出版物。 2006 年 5 月，Siegenthaler 博士加入了 UCSF Sam Pleasure 博士的实验室，在那里她开始研究脑膜分泌因子在新皮质发育中的作用的项目。她利用无法形成完整脑膜且前脑发育严重缺陷的 Foxc1 突变小鼠表明，脑膜来源的视黄酸是皮质生成过程中驱动神经元生成的关键元素。这项研究以第一作者的身份发表在《细胞》杂志上。 Siegenthaler 博士还生成了有关 Foxc1 突变体脑血管缺陷的大量数据，她致力于制定一项独立的研究计划，重点了解不同的结构和细胞类型如何促进脑血管系统的形成。西根塔勒博士制定了全面的职业发展计划来实现她的职业目标。在 K99 指导阶段，西根塔勒博士将继续受益于她的资助者 Sam Pleasure 博士的指导和指导，并在完成研究计划概述的具体目标时获得新技能。 K99阶段获得的实验数据和技术对于R00阶段计划的研究非常有价值。 Siegenthaler 博士的长期目标是开发一个全面、多方面的研究计划，研究胚胎和成人脑膜的发育和功能、Foxc1 在血管周围细胞中的功能作用，以及大脑发育过程中神经组织和脉管系统之间的相互作用。环境。西根塔勒博士在加州大学旧金山分校使命湾校区 Rock Hall 5 楼拥有自己的工作空间和办公桌。她可以完全使用她的导师 Pleasure 博士的设备和空间，包括一般实验室设备、离心机、冰柜、解剖室以及相邻的组织培养罩和培养箱、显微镜以及动物设施中的空间。她还可以使用 UCSF 的核心设施，包括细胞分选和实时 PCR 设备。 Siegenthaler 博士拥有完成 K99 阶段概述的实验所需的设备和设施。她的研究将在加州大学旧金山分校进行，这是一家备受推崇的研究机构，致力于通过生物医学研究、患者护理和教育来改善个人健康。使命湾校区的研究设施是加州大学旧金山分校为提高和扩大其研究能力而做出的重大努力的一部分。与邻近的格拉德斯通研究所一起，使命湾校区为西根塔勒博士提供了充足的机会参加研讨会、演讲、期刊俱乐部，并与教职员工举行非正式会议，这将极大地促进她的独立研究生涯的培训和准备。研究。该提案利用 Foxc1 突变小鼠（其血管和大脑发育存在缺陷）来进一步了解大脑血管系统的形成方式。 K99 阶段的实验旨在了解 Foxc1 突变体中脑膜的缺失和前脑发育缺陷如何不同地导致血管畸形。 R00阶段的实验将研究内皮细胞上脑膜衍生信号的潜在靶标、Foxc1在与大脑内部和周围血管系统相关的壁细胞的分化和功能中的细胞自主作用，并进一步探索神经衍生信号在发育中皮层血管化中的作用。 Foxc1 在发育中的胚胎和成人中由神经嵴衍生的脑膜细胞和壁细胞（周细胞和平滑肌细胞的统称）表达。然而 Foxc1 突变小鼠在皮质发育和前脑脉管系统的形成方面都存在严重缺陷。我之前已经证明，背侧前脑发育缺陷是由于脑膜来源的视黄酸的损失造成的。我的初步证据表明，脑膜中的视黄酸还调节前脑周围的内皮细胞增殖和血管形成（称为神经周围血管丛（PNVP））。具体目标 1 中的实验将专门解决视黄酸在 PNVP 形成中的作用。在具体目标 2 中，我将解决 Foxc1 在 CNS 壁细胞分化和功能中的作用使用 Foxc1 的壁细胞特异性消融。除了 PNVP 缺陷之外，Foxc1 突变体中皮质内脉管系统也无法正常形成。在第三个目标中，我将检验这样的假设：Foxc1 突变体的皮质内血管表型是由于背侧前脑重要的血管生成线索的丧失造成的。公众健康相关性：中风是长期残疾和死亡的一个重要原因，可能是由胎儿发育过程中发生的先天性血管缺陷引起的。该提案中的研究旨在显着扩大我们对控制大脑皮层内部和周围脉管系统形成的因素的理解。了解脑血管系统的形成方式不仅可以阐明先天性血管畸形的病因，还可以进一步了解中风恢复期间可能重新激活的发育性血管生成途径。