The role of LTBP2 in glaucoma

LTBP2在青光眼中的作用

基本信息

  • 批准号:
    10608873
  • 负责人:
  • 金额:
    $ 23.33万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-03-01 至 2025-02-28
  • 项目状态:
    未结题

项目摘要

Summary: A unique animal model of glaucoma with spontaneously arising mutation in LTBP2 has been established. This gene is implicated in heterogeneous glaucoma phenotypes, including human primary congenital glaucoma (PCG) as well as some forms of adult-onset open angle glaucoma. As the only known large animal homolog of inherited glaucoma in humans, this model has considerable potential for translational research. Posterior segment pathology has been extensively characterized and closely recapitulates features of human glaucomatous optic neuropathy. However, the role played by LTBP2 in the eye remains unknown and the precise cellular and molecular mechanisms responsible for the underlying elevated intraocular pressure (IOP) in this form of glaucoma remain unresolved. The objective of this proposal is to identify and localize, as potential targets for therapeutic intervention, key pathobiological mechanisms that contribute to both early onset and progressive IOP elevation in this model. In addition to perturbing LTBP2’s acknowledged role in microfibril assembly, enhanced TGF beta signaling, contributing to extracellular matrix (ECM) accumulation within the trabecular meshwork (TM) has been proposed as a mechanism for IOP elevation in this “microfibrillopathy”. However, preliminary studies in our animal model have not established whether significant increase in aqueous humor TGF beta concentrations represent a cause or effect of IOP elevation. Our central hypothesis is that LTBP2 is both an important regulator of outflow pathway development and remodeling in the perinatal period and a regulator of TM cell and ECM biology and pro-fibrotic pathways throughout life, extending beyond development. We will pursue two specific Aims: Aim 1: To determine the effects of absent or reduced LTBP2 expression on development of proximal and distal aqueous outflow pathways, we will test the hypothesis that LTBP2 plays an important role in outflow pathway development and remodeling using a combination of in vivo and in situ approaches to examine distal outflow morphology and ultrastructure of the proximal outflow pathway (TM and juxtacanalicular tissue) and ECM components of these pathways in wildtype and LTBP2+/- and LTBP2-/- eyes. Aim 2: To determine the pathological effects of absent or reduced LTBP2 expression on TM cell (TMC) biology, we will use TMC cultures derived from wildtype, LTBP2+/- and LTBP2-/- eyes. In Aim 2, we will test the hypotheses that reduced LTBP2 expression will a) negatively impact TMC attachment and proliferation in vitro and b) enhance the pathologic effects of TGFβ on actin cytoskeleton and promotion of ECM fibrosis. Successful completion of these Aims will generate new knowledge on the complex role of LTBP2 in physiology and pathology of the aqueous outflow pathways, providing a critical foundation to advance our overall goal of designing and testing innovative therapeutic approaches to glaucoma in our unique translational model.
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项目成果

期刊论文数量(0)
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Gillian Jane McLellan其他文献

Gillian Jane McLellan的其他文献

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{{ truncateString('Gillian Jane McLellan', 18)}}的其他基金

Disease Mechanisms at the Intersection of Glaucoma and Alzheimer's Disease
青光眼和阿尔茨海默病交叉的疾病机制
  • 批准号:
    10306895
  • 财政年份:
    2021
  • 资助金额:
    $ 23.33万
  • 项目类别:
Enhanced backscattering instrument for assessing optical biomarkers of glaucoma
用于评估青光眼光学生物标志物的增强型反向散射仪器
  • 批准号:
    9764362
  • 财政年份:
    2018
  • 资助金额:
    $ 23.33万
  • 项目类别:
Therapeutic Inhibition of Optic Nerve Head Gliosis and Fibrosis in Glaucoma
青光眼视神经乳头胶质增生和纤维化的治疗抑制
  • 批准号:
    10202607
  • 财政年份:
    2017
  • 资助金额:
    $ 23.33万
  • 项目类别:
Therapeutic Inhibition of Optic Nerve Head Gliosis and Fibrosis in Glaucoma
青光眼视神经乳头胶质增生和纤维化的治疗抑制
  • 批准号:
    9382204
  • 财政年份:
    2017
  • 资助金额:
    $ 23.33万
  • 项目类别:
Structural and Functional Characterization of a Novel Model for Glaucoma Research
青光眼研究新模型的结构和功能表征
  • 批准号:
    7685380
  • 财政年份:
    2008
  • 资助金额:
    $ 23.33万
  • 项目类别:
Structural and Functional Characterization of a Novel Model for Glaucoma Research
青光眼研究新模型的结构和功能表征
  • 批准号:
    7872895
  • 财政年份:
    2008
  • 资助金额:
    $ 23.33万
  • 项目类别:
Structural and Functional Characterization of a Novel Model for Glaucoma Research
青光眼研究新模型的结构和功能表征
  • 批准号:
    8288212
  • 财政年份:
    2008
  • 资助金额:
    $ 23.33万
  • 项目类别:
Structural and Functional Characterization of a Novel Model for Glaucoma Research
青光眼研究新模型的结构和功能表征
  • 批准号:
    8098016
  • 财政年份:
    2008
  • 资助金额:
    $ 23.33万
  • 项目类别:
Structural and Functional Characterization of a Novel Model for Glaucoma Research
青光眼研究新模型的结构和功能表征
  • 批准号:
    7531975
  • 财政年份:
    2008
  • 资助金额:
    $ 23.33万
  • 项目类别:
UW Vision Research Core 3 - Animal Models and Eye Organ Culture
华盛顿大学视觉研究核心 3 - 动物模型和眼器官培养
  • 批准号:
    10273754
  • 财政年份:
    2005
  • 资助金额:
    $ 23.33万
  • 项目类别:

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