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

基本信息

  • 批准号:
    8726402
  • 负责人:
  • 金额:
    $ 38.1万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
描述(由申请人提供):我们的目标是确定控制眼前节发育的遗传网络,并了解这些网络的破坏如何导致眼前节结构和功能的缺陷。我们的目的是测试前节组织中同源结构域转录因子PITX2的功能,这些组织在PITX2突变的人类患者中最常见。我们的中心假设是PITX 2调节遗传网络,这些网络是指定正常角膜细胞命运、将血管排除在发育和成熟角膜之外以及调节虹膜和虹膜角膜角结构内的细胞增殖和谱系指定所需的。我们的假设是根据对时间基因敲除小鼠的分析产生的初步数据制定的。这项研究的基本原理是,在角膜、虹膜和虹膜角膜角的正常发育中,PITX2调控的遗传网络的知识将促进我们对眼前段发育不全和相关病理的理解,包括眼内压升高。我们将通过追求三个具体目标来检验我们的假设:1)检验Pitx2是角膜细胞命运的特化和维持所必需的假设,2)检验Pitx2是防止血管生长到发育和成熟角膜中所必需的假设,以及3)检验Pitx2是虹膜和虹膜角膜角结构的正常发育所必需的假设。在前两个目标下,申请人手中已经可行的时间敲除策略将用于在角膜发育开始时消融Pitx2,之后将使用成熟的方法评估角膜谱系和血管生长。在第三个目标下,类似的时间敲除方法(在申请人手中也被确立为可行的)将用于在虹膜和虹膜角膜角发育开始时消融Pitx2,并且将确定对结构发育的后果。预期的结果是PITX2在角膜,虹膜和虹膜角膜角发育中的基本功能将被确定。该方法是创新的,因为它利用了时间基因敲除策略,以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重要的后形成的结构在眼前节。这项研究意义重大,因为它将纵向推进和扩展对眼前节结构在发育过程中如何形成的理解。最终,这样的知识将提供洞察如何前段发育不良有助于视力丧失。

项目成果

期刊论文数量(0)
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PHILIP J GAGE其他文献

PHILIP J GAGE的其他文献

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{{ truncateString('PHILIP J GAGE', 18)}}的其他基金

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:
    8527780
  • 财政年份:
    2002
  • 资助金额:
    $ 38.1万
  • 项目类别:
Pitx2: Molecular Mechanisms in Eye Development and Disease
Pitx2:眼睛发育和疾病的分子机制
  • 批准号:
    7633163
  • 财政年份:
    2002
  • 资助金额:
    $ 38.1万
  • 项目类别:
Pitx2: Molecular Mechanisms in Eye Development and Disease
Pitx2:眼睛发育和疾病的分子机制
  • 批准号:
    7465357
  • 财政年份:
    2002
  • 资助金额:
    $ 38.1万
  • 项目类别:
Pitx2: Molecular mechanisms in eye development & disease
Pitx2:眼睛发育的分子机制
  • 批准号:
    6507295
  • 财政年份:
    2002
  • 资助金额:
    $ 38.1万
  • 项目类别:
Pitx2: Molecular Mechanisms in Eye Development and Disease
Pitx2:眼睛发育和疾病的分子机制
  • 批准号:
    7143638
  • 财政年份:
    2002
  • 资助金额:
    $ 38.1万
  • 项目类别:
Identification of PITX2-dependent mechanisms in the developing and mature cornea
鉴定发育和成熟角膜中 PITX2 依赖性机制
  • 批准号:
    9381229
  • 财政年份:
    2002
  • 资助金额:
    $ 38.1万
  • 项目类别:
Pitx2: Molecular mechanisms in eye development & disease
Pitx2:眼睛发育的分子机制
  • 批准号:
    6652638
  • 财政年份:
    2002
  • 资助金额:
    $ 38.1万
  • 项目类别:
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
  • 财政年份:
    2002
  • 资助金额:
    $ 38.1万
  • 项目类别:
Pitx2: Molecular Mechanisms in Eye Development and Disease
Pitx2:眼睛发育和疾病的分子机制
  • 批准号:
    7881490
  • 财政年份:
    2002
  • 资助金额:
    $ 38.1万
  • 项目类别:
Pitx2: Molecular mechanisms in eye development & disease
Pitx2:眼睛发育的分子机制
  • 批准号:
    6786578
  • 财政年份:
    2002
  • 资助金额:
    $ 38.1万
  • 项目类别:

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