Molecular Induction of Corneal Endothelial Proliferation

角膜内皮增殖的分子诱导

基本信息

  • 批准号:
    7664111
  • 负责人:
  • 金额:
    $ 10.01万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2000
  • 资助国家:
    美国
  • 起止时间:
    2000-08-01 至 2009-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION: Human corneal endothelial cells (HCEC) are inhibited in G1-phase of the cell cycle. This prevents cell division from replacing dead cells and can result in critically low cell density. Our LONG-TERM GOALS are to identify the molecular basis for this inhibition and to develop methods to stimulate proliferation to increase cell density. HCEC at all donor ages possess proliferative capacity; however, there is an intrinsic, age-related decrease in their response to serum, implying increased inhibition with increasing donor age. The GOAL of our studies is to identify the inhibitory mechanisms responsible for this age-related decrease in serum responsiveness. An exciting, novel approach will be used based on studies of replicative senescence. We will test the HYPOTHESIS that the age-related decrease in ability of HCEC to respond to serum is due to increased inhibition by the cyclin-dependent kinase inhibitor, p21CIP1 (p21). Both ex vivo corneas and cultured HCEC from young (<30yo) and older donors (>50yo) will be used in these studies. In Aim 1, image analysis of Mcm2 expression will permit calculation of the percent of HCEC in each age-group that are competent to replicate in response to serum. In Aim 2, Western blots, real-time PCR, and mobility shift assays will test if there is an age-related decrease in the activity of key G1-phase regulators that suggests increased inhibition by p21. Aim 3 will test if p21 siRNA treatment of cultured cells will promote proliferation in HCEC from OLDER donors. Aim 4 will test if p21 siRNA treatment will promote an increase in endothelial cell density in ex vivo corneas from OLDER donors. Aims 3 and 4 will use staining for cell cycle markers and direct cell counts to document proliferation. In Aim 4, image analysis will test if p21 siRNA treatment will promote an increase in cell density in corneas with densities <1500 cells/mm2. If our hypothesis is correct, molecular approaches could tap the residual proliferative capacity of HCEC in older donors by decreasing p21 expression.
描述:人角膜内皮细胞(HCEC)在细胞周期的G1期受到抑制。这阻止了细胞分裂取代死细胞,并可能导致极低的细胞密度。我们的长期目标是确定这种抑制的分子基础,并开发刺激增殖以增加细胞密度的方法。所有供体年龄的HCEC都具有增殖能力;然而,它们对血清的反应存在内在的、与年龄相关的降低,这意味着随着供体年龄的增加抑制作用增加。我们研究的目标是确定与年龄相关的血清反应性降低的抑制机制。一个令人兴奋的,新的方法将使用基于复制衰老的研究。我们将检验以下假设:年龄相关的HCEC对血清反应能力的降低是由于细胞周期蛋白依赖性激酶抑制剂p21 CIP 1(p21)的抑制作用增强。这些研究将使用来自年轻(<30岁)和老年供体(> 50岁)的离体角膜和培养的HCEC。在目标1中,Mcm 2表达的图像分析将允许计算每个年龄组中能够响应血清复制的HCEC的百分比。在目标2中,蛋白质印迹、实时PCR和迁移率变动分析将测试关键G1期调节因子的活性是否存在年龄相关的降低,这表明p21的抑制增加。目的3将测试培养细胞的p21 siRNA处理是否会促进来自老年供体的HCEC的增殖。目的4将测试p21 siRNA处理是否会促进来自老年供体的离体角膜中内皮细胞密度的增加。目标3和4将使用细胞周期标志物染色和直接细胞计数来记录增殖。在目标4中,图像分析将测试p21 siRNA处理是否会促进密度<1500个细胞/mm 2的角膜中细胞密度的增加。如果我们的假设是正确的,分子方法可以通过降低p21表达来挖掘老年供体中HCEC的残余增殖能力。

项目成果

期刊论文数量(0)
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NANCY C. JOYCE其他文献

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{{ truncateString('NANCY C. JOYCE', 18)}}的其他基金

Differentiation of Cord Blood Mesenchymal Stem Cells to Corneal Endothelium
脐带血间充质干细胞向角膜内皮的分化
  • 批准号:
    7570902
  • 财政年份:
    2009
  • 资助金额:
    $ 10.01万
  • 项目类别:
Differentiation of Cord Blood Mesenchymal Stem Cells to Corneal Endothelium
脐带血间充质干细胞向角膜内皮的分化
  • 批准号:
    7844831
  • 财政年份:
    2009
  • 资助金额:
    $ 10.01万
  • 项目类别:
Molecular Induction of Corneal Endothelial Proliferation
角膜内皮增殖的分子诱导
  • 批准号:
    7495410
  • 财政年份:
    2000
  • 资助金额:
    $ 10.01万
  • 项目类别:
MOLECULAR INDUCTION OF CORNEAL ENDOTHELIAL PROLIFERATION
角膜内皮增殖的分子诱导
  • 批准号:
    6402635
  • 财政年份:
    2000
  • 资助金额:
    $ 10.01万
  • 项目类别:
Molecular Induction of Corneal Endothelial Proliferation
角膜内皮增殖的分子诱导
  • 批准号:
    7271203
  • 财政年份:
    2000
  • 资助金额:
    $ 10.01万
  • 项目类别:
Molecular Induction of Corneal Endothelial Proliferation
角膜内皮增殖的分子诱导
  • 批准号:
    7099520
  • 财政年份:
    2000
  • 资助金额:
    $ 10.01万
  • 项目类别:
Molecular Induction of Corneal Endothelial Proliferation
角膜内皮增殖的分子诱导
  • 批准号:
    7475048
  • 财政年份:
    2000
  • 资助金额:
    $ 10.01万
  • 项目类别:
MOLECULAR INDUCTION OF CORNEAL ENDOTHELIAL PROLIFERATION
角膜内皮增殖的分子诱导
  • 批准号:
    6189861
  • 财政年份:
    2000
  • 资助金额:
    $ 10.01万
  • 项目类别:
MOLECULAR INDUCTION OF CORNEAL ENDOTHELIAL PROLIFERATION
角膜内皮增殖的分子诱导
  • 批准号:
    6524981
  • 财政年份:
    2000
  • 资助金额:
    $ 10.01万
  • 项目类别:
Molecular Induction of Corneal Endothelial Proliferation
角膜内皮增殖的分子诱导
  • 批准号:
    6965914
  • 财政年份:
    2000
  • 资助金额:
    $ 10.01万
  • 项目类别:

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