Control of Trabecular Meshwork Cytoskeleton

小梁网细胞骨架的控制

基本信息

  • 批准号:
    10316183
  • 负责人:
  • 金额:
    $ 44.08万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2006
  • 资助国家:
    美国
  • 起止时间:
    2006-09-15 至 2024-12-31
  • 项目状态:
    已结题

项目摘要

The long-term objective of this grant is to identify how to modulate αvβ3 integrin signaling pathways in order to develop therapeutic targets to control intraocular pressure (IOP) in glaucoma. The glaucomas, which lead to irreversible loss of retinal ganglion cells, affect approximately 67 million people worldwide. They are commonly associated with elevated levels of intraocular pressure (IOP) due to a reduction in aqueous humor outflow from the trabecular meshwork (TM). One of the major risk factors that has emerged as an important regulatory mechanism for outflow facility is the actin cytoskeleton. It controls a number of key biological processes involved in maintaining normal outflow facility including contractility, phagocytosis, and deposition of the extracellular matrix. Integrins play a central role in regulating these cytoskeleton-mediated activities and our studies suggest that dysregulation of the αvβ3 integrin causes the major phenotypic changes associated with glaucoma including decreased phagocytosis, increased extracellular matrix deposition, CLAN formation and an elevation in IOP. We propose that this integrin is activated in glaucoma by elevated levels of TGFβ2 or following treatments with glucocorticoids, like dexamethasone (DEX). In this grant, we plan to use RNAseq studies to identify the factors upregulated by DEX or TGFβ2 that activate αvβ3 integrin and proximity ligation assays to determine if these factors are associated with the integrin adhesome. We also plan to demonstrate that an NRON/NFAT complex controls DEX-induced activation of αvβ3 integrin and the secondary glucocorticoid response involved in steroid-induced glaucoma. Finally, we plan to show that the responses to DEX (ECM formation, IOP elevation, and outflow facility) are affected by the activated state of αvβ3 integrin in vivo, not just its expression level. To test this last hypothesis we plan to use a tamoxifen inducible CreERcag-β3 integrinflox/flox mouse to knock down αvβ3 integrin expression in the mouse TM. Adenoviral (Ad5) vectors expressing 3 different activated states of αvβ3 integrin (wildtype, inactive and constitutively active) will be used to alter the activity levels of αvβ3 integrins in vivo. The proposed studies are the first to demonstrate that changes in a specific integrin signaling pathway can affect IOP, outflow facility, and ECM formation in vivo. They will enhance our understanding of how integrin signaling events are controlled in the TM and how this affects the cytoskeletal events (ECM deposition, cell contractility and phagocytosis) that regulate outflow facility. Understanding how integrins contribute to the regulation of these processes is important because it will enable us to provide new therapeutic targets to regulate the cytoskeleton in order to restore homeostasis and decrease IOP.
该基金的长期目标是确定如何调节α v β 3整合素信号传导 因此,本发明的目的是研究青光眼的治疗途径,以便开发控制青光眼中的眼内压(IOP)的治疗靶点。的 视网膜神经节细胞的不可逆损失,影响大约6700万人 国际吧它们通常与眼内压(IOP)水平升高有关,这是由于眼内压降低导致的。 在从小梁网流出的房水中(TM)。出现的主要风险因素之一是 作为流出便利性的重要调节机制的是肌动蛋白细胞骨架。它控制着许多键 参与维持正常流出功能的生物学过程,包括收缩性、吞噬作用和 细胞外基质的沉积。整合素在调节这些细胞因子介导的细胞凋亡中起着重要作用。 活性和我们的研究表明,α v β 3整合素的失调引起主要的表型变化, 与青光眼相关,包括吞噬作用降低、细胞外基质沉积增加、CLAN 形成和IOP升高。我们认为,这种整合素在青光眼中是通过升高水平的 TGF β 2或糖皮质激素治疗后,如地塞米松(DEX)。 在这项资助中,我们计划使用RNAseq研究来鉴定DEX或TGF β 2上调的因子, 激活α v β 3整联蛋白和邻近连接试验,以确定这些因子是否与 整合素粘附体。我们还计划证明NRON/NFAT复合物控制DEX诱导的 α v β 3整合素的激活和继发性糖皮质激素反应参与类固醇诱导的青光眼。 最后,我们计划表明对DEX的反应(ECM形成,IOP升高和流出设施)是 受体内α v β 3整合素活化状态的影响,而不仅仅是其表达水平。为了验证最后一个假设 我们计划使用他莫昔芬诱导的CreERcag-β 3整合素flox/flox小鼠来敲低α v β 3整合素 在小鼠TM中的表达。表达3种不同活化状态的α v β 3整联蛋白的腺病毒(Ad5)载体 (野生型、无活性和组成型活性)将用于改变体内α v β 3整联蛋白的活性水平。 这项研究首次证明了特定整合素信号传导的变化 在体内,该通路可影响IOP、流出便利性和ECM形成。它们将增进我们对 整合素信号事件如何在TM中控制,以及这如何影响细胞骨架事件(ECM 沉积、细胞收缩性和吞噬作用),其调节流出设施。了解整合素如何 有助于调节这些过程是重要的,因为它将使我们能够提供新的治疗方法, 靶向调节细胞骨架,以恢复稳态并降低IOP。

项目成果

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Donna M Peters其他文献

Donna M Peters的其他文献

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{{ truncateString('Donna M Peters', 18)}}的其他基金

NFAT and fibrosis in the trabecular meshwork
NFAT 和小梁网纤维化
  • 批准号:
    10630268
  • 财政年份:
    2022
  • 资助金额:
    $ 44.08万
  • 项目类别:
NFAT and fibrosis in the trabecular meshwork
NFAT 和小梁网纤维化
  • 批准号:
    10436632
  • 财政年份:
    2022
  • 资助金额:
    $ 44.08万
  • 项目类别:
Targeting the Anterior Segment with Homing Peptides from Phage Display
使用噬菌体展示的归巢肽靶向眼前节
  • 批准号:
    8487758
  • 财政年份:
    2013
  • 资助金额:
    $ 44.08万
  • 项目类别:
Targeting the Anterior Segment with Homing Peptides from Phage Display
使用噬菌体展示的归巢肽靶向眼前节
  • 批准号:
    8651496
  • 财政年份:
    2013
  • 资助金额:
    $ 44.08万
  • 项目类别:
Integrin Signaling in the Trabecular Meshwork
小梁网中的整合素信号传导
  • 批准号:
    8264354
  • 财政年份:
    2010
  • 资助金额:
    $ 44.08万
  • 项目类别:
Integrin Signaling in the Trabecular Meshwork
小梁网中的整合素信号传导
  • 批准号:
    7862023
  • 财政年份:
    2010
  • 资助金额:
    $ 44.08万
  • 项目类别:
Integrin Signaling in the Trabecular Meshwork
小梁网中的整合素信号传导
  • 批准号:
    8059627
  • 财政年份:
    2010
  • 资助金额:
    $ 44.08万
  • 项目类别:
Control of Trabecular Meshwork Cytoskeleton
小梁网细胞骨架的控制
  • 批准号:
    7489937
  • 财政年份:
    2006
  • 资助金额:
    $ 44.08万
  • 项目类别:
Control of Trabecular Meshwork Cytoskeleton
小梁网细胞骨架的控制
  • 批准号:
    7141361
  • 财政年份:
    2006
  • 资助金额:
    $ 44.08万
  • 项目类别:
Control of Trabecular Meshwork Cytoskeleton
小梁网细胞骨架的控制
  • 批准号:
    8691189
  • 财政年份:
    2006
  • 资助金额:
    $ 44.08万
  • 项目类别:

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