Essential functions of PITX2 in cornea, iris, and iridocorneal angle development

PITX2 在角膜、虹膜和虹膜角膜角发育中的基本功能

• 批准号: 8183946
• 负责人: PHILIP J GAGE
• 金额: $ 38.88万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8183946
• 关键词: Ablation; Adult; Affect; Angiogenic Factor; Anterior; Blindness; Blood Vessels; Cell Lineage; Cell Proliferation; Cell Survival; Cells; Cornea; Data; Defect; Development; Diagnostic; Equilibrium; Exclusion; Eye; Eye Development; Eye diseases; Future; Genetic; Glaucoma; Goals; Growth; Hand; Human; Iris; Knock-out; Knockout Mice; Knowledge; Laboratories; Lead; Maintenance; Mission; Molecular; Mutation; Normal Cell; Outcome; Pathogenesis; Pathology; Patients; Phenotype; Physiologic Intraocular Pressure; Public Health; Regulation; Research; Risk Factors; Role; Signal Transduction; Staging; Structure; Testing; Time; Tissues; To specify; Vascularization; base; disability; gene function; high risk; homeodomain; human disease; innovation; insight; knockout animal; knockout gene; mouse model; mutant; prevent; transcription factor; treatment strategy

DESCRIPTION (provided by applicant): Our goal is to identify the genetic networks governing ocular anterior segment development and to understand how disruption of these networks leads to defects in anterior segment structure and function. Our objective is to test the functions of the homeodomain transcription factor PITX2 in anterior segment tissues that are most commonly affected in human patients with PITX2 mutations. Our central hypothesis is that PITX2 regulates genetic networks that are required to specify normal corneal cell fates, exclude blood vessels from the developing and mature cornea, and regulate cell proliferation and lineage specification within the iris and structures of the iridocorneal angle. Our hypothesis was formulated on the basis of preliminary data generated by analysis of temporal knockout mice. The rationale for the proposed research is that knowledge of the genetic networks regulated by PITX2 in normal development of the cornea, iris, and iridocorneal angle will advance our understanding of anterior segment dysgenesis and associated pathologies, including elevated intraocular pressure. We will test our hypothesis by pursuing three specific aims: 1) Test the hypothesis that Pitx2 is required for specification and maintenance of corneal cell fates, 2) Test the hypothesis that Pitx2 is required to prevent vascular growth into the developing and mature cornea, and 3) Test the hypothesis that Pitx2 is required for normal development of the iris and structures of the iridocorneal angle. Under the first two aims, a temporal knockout strategy, which is already feasible in the applicant's hands, will be used to ablate Pitx2 at the beginning of corneal development, after which corneal lineages and vascular growth will be assessed using well-established approaches. Under the third aim, an analogous temporal knockout approach, also established as feasible in the applicant's hands, will be used to ablate Pitx2 at the beginning of iris and iridocorneal angle development and the consequences on development of the structures will be determined. The expected outcome is that essential functions of PITX2 in the development of the cornea, iris, and iridocorneal angle will be identified. The approach is innovative because it utilizes a temporal gene knockout strategy to overcome the limitations of global and tissue-specific Pitx2 knockout animals, thereby permitting us to study important later-forming structures in the anterior segment. The proposed research is significant because it will vertically advance and expand understanding of how anterior segment structures are formed during development. Ultimately, such knowledge will provide insights into how anterior segment dysgenesis contributes to vision loss. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health, because understanding the molecular mechanisms governing normal anterior segment development will advance our knowledge of the pathogenesis and vision loss resulting from anterior segment dysgenesis. Thus, the proposed research is relevant to the part of NIH's mission that pertains to developing fundamental knowledge that will ultimately help to reduce the burdens of human disease and disability.

描述（由申请人提供）：我们的目标是确定控制眼前部分开发的遗传网络，并了解这些网络的破坏如何导致前部段结构和功能中的缺陷。我们的目的是测试同源域转录因子PITX2在前节组织中的功能，这些功能最常见于PITX2突变的人类患者。我们的中心假设是，PITX2调节了指定正常角膜细胞命运，将血管排除在发育和成熟的角膜中所需的遗传网络，并调节虹膜和虹膜内部角度结构内的细胞增殖和谱系规范。我们的假设是根据分析时间基因敲除小鼠产生的初步数据提出的。拟议研究的理由是，在角膜，虹膜和虹膜核角的正常发育中，对PITX2调节的遗传网络的了解将使我们对前部段失调和相关病理的理解，包括眼内压升高。我们将通过追求三个具体目的来检验假设：1）检验以下假设：PITX2对于角膜细胞命运的规范和维持所必需的假设，2）检验以下假设：PITX2需要预防发育中和成熟角膜的血管生长，以及3）测试PITX2对于Iris和Iris iriDococorneal eyneal ondococorocorneal的正常发育所需的假说。在前两个目标下，在角膜发育开始时，将使用一种暂时的敲除策略，它将在申请人的手中可行，用于烧蚀Pitx2，之后，将使用完善的方法来评估角膜谱系和血管生长。在第三个目标下，在申请人手中也可行的类似的时间敲除方法将在虹膜和虹膜角发育开始时燃烧pitx2，并将确定结构发展的后果。预期的结果是，将确定PITX2在角膜，虹膜和虹膜角度的发展中的基本功能。这种方法具有创新性，因为它利用颞基因敲除策略来克服全球和组织特异性PITX2敲除动物的局限性，从而使我们能够研究前部段中重要的后期形成结构。拟议的研究之所以重要，是因为它将垂直提高和扩展对开发过程中前部结构的形成方式的理解。最终，此类知识将提供有关前部失去障碍有助于视力丧失的见解。 公共卫生相关性：拟议的研究与公共卫生有关，因为了解正常前部开发的分子机制将提高我们对前部段失去发病障碍引起的发病机理和视力丧失的了解。因此，拟议的研究与NIH使命的一部分有关，该任务与发展基本知识有关，最终将有助于减轻人类疾病和残疾的负担。