DNA Damage and Neurodegeneration in Cockayne Syndrome

科凯恩综合征中的 DNA 损伤和神经变性

基本信息

项目摘要

DESCRIPTION (provided by applicant): Cockayne syndrome (CS) is a progressive childhood neurodegenerative disorder associated with a DNA repair defect. Two genes, CSA and CSB, are specifically involved in the CS disorder. These genes are involved in nucleotide excision repair (NER) of ultraviolet damage (UV) in transcriptionally active genes (transcription coupled repair, TCP). Cs-a and Cs-b mice have much milder neurological symptoms than human patients, but a greater risk for cancer that is not usually evident in humans. We have found that crossing Cs-b mice with Xp-c mice, that are defective in NER of nontranscribed regions of the genome, increases the severity and reduces the age of onset of neurodegeneration in animals that are homozygous or heterozygous in both genes but without necessarily compromising UV sensitivity. This has resulted in mouse strains that reflect the range of severity of human CS patients and can be used as models of neurodegeneration that we will compare in detail with the human syndrome. Not all the symptoms of CS patients are however easily related to repair deficiencies, so we hypothesize that there are additional pathways relevant to the disease particularly those that are downstream consequences of a common defect in ubiquitin ligase associated with the CSA and CSB gene products. We have found that the CSB defect results in altered expression of cell cycle and anti-angiogenic genes and proteins, and more programmed cell death that are relevant to the impaired development and progressive neurodegeneration. We therefore propose that, in Aim I, we will determine whether the mouse Cs-b x Xp-c crosses recapitulate the pathology of the human disease. We will determine the specific sites of programmed cell death and whether Purkinje cell loss is a primary event or due to loss of progenitor or associated cell types. We will determine whether neurodegeneration is consistent with premature cell cycle entry and apoptosis from chronic oxidative injury. In Aim II, we will examine global and transcription coupled repair in human CS cells and mouse fibroblasts from our mouse strains and differentiation-associated repair in mouse cells of neuronal origin following damage from reactive oxygen, to identify the contributions of these repair genes to neurodegeneration. In Aim III we will determine the roles played by protein targets of CS-dependent ubiquitylation that we have identified, especially those whose over-expression may have pathological consequences. We will emphasize those targets previously identified, such as p21 and collagen 15a1, for their roles in development and neurodegeneration. Successful conclusion of these studies will expand our knowledge of mechanisms of neurodegeneration and lay groundwork for development of therapeutic approaches for CS patients.
描述(由申请人提供):科凯恩综合征(CS)是一种与DNA修复缺陷相关的进行性儿童神经退行性疾病。两个基因,CSA和CSB,与CS疾病有关。这些基因参与转录活性基因紫外线损伤(UV)的核苷酸切除修复(NER)(转录偶联修复,TCP)。Cs-a和Cs-b小鼠的神经症状比人类患者轻得多,但患癌症的风险更高,这在人类中通常不明显。我们发现,在基因组非转录区域的NER中有缺陷的Cs-b小鼠与Xp-c小鼠杂交,增加了两种基因纯合或杂合的动物神经变性的严重程度并降低了发病年龄,但不一定影响紫外线敏感性。这导致小鼠品系反映了人类CS患者的严重程度范围,可以用作我们将与人类综合征详细比较的神经变性模型。然而,并非所有CS患者的症状都容易与修复缺陷相关,因此我们假设存在与该疾病相关的其他途径,特别是与CSA和CSB基因产物相关的泛素连接酶常见缺陷的下游后果。我们发现CSB缺陷导致细胞周期和抗血管生成基因和蛋白的表达改变,以及与发育受损和进行性神经变性相关的更多程序性细胞死亡。因此,我们建议,在Aim I中,我们将确定小鼠Cs-b x Xp-c杂交是否概括了人类疾病的病理。我们将确定程序性细胞死亡的具体部位,以及浦肯野细胞损失是原发性事件还是由于祖细胞或相关细胞类型的损失。我们将确定神经变性是否与慢性氧化损伤引起的细胞周期过早进入和细胞凋亡一致。在Aim II中,我们将研究来自小鼠品系的人类CS细胞和小鼠成纤维细胞的全局修复和转录偶联修复,以及小鼠神经元源细胞在活性氧损伤后的分化相关修复,以确定这些修复基因对神经变性的贡献。在Aim III中,我们将确定我们已经确定的cs依赖性泛素化蛋白靶点所起的作用,特别是那些过度表达可能具有病理后果的蛋白靶点。我们将强调那些先前确定的靶点,如p21和胶原15a1,它们在发育和神经变性中的作用。这些研究的成功结论将扩大我们对神经退行性变机制的认识,并为开发CS患者的治疗方法奠定基础。

项目成果

期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Physical and functional interaction between DDB and XPA in nucleotide excision repair.
  • DOI:
    10.1093/nar/gkn964
  • 发表时间:
    2009-02
  • 期刊:
  • 影响因子:
    14.9
  • 作者:
    Wakasugi M;Kasashima H;Fukase Y;Imura M;Imai R;Yamada S;Cleaver JE;Matsunaga T
  • 通讯作者:
    Matsunaga T
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JAMES E CLEAVER其他文献

JAMES E CLEAVER的其他文献

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{{ truncateString('JAMES E CLEAVER', 18)}}的其他基金

DNA Damage and Neurodegeneration in Cockayne Syndrome
科凯恩综合征中的 DNA 损伤和神经变性
  • 批准号:
    7439076
  • 财政年份:
    2006
  • 资助金额:
    $ 33.75万
  • 项目类别:
DNA Damage and Neurodegeneration in Cockayne Syndrome
科凯恩综合征中的 DNA 损伤和神经变性
  • 批准号:
    7252003
  • 财政年份:
    2006
  • 资助金额:
    $ 33.75万
  • 项目类别:
DNA Damage and Neurodegeneration in Cockayne Syndrome
科凯恩综合征中的 DNA 损伤和神经变性
  • 批准号:
    7141167
  • 财政年份:
    2006
  • 资助金额:
    $ 33.75万
  • 项目类别:
Cutaneous oncology program
皮肤肿瘤学项目
  • 批准号:
    6211795
  • 财政年份:
    1999
  • 资助金额:
    $ 33.75万
  • 项目类别:
XP VARIANT--A HUMAN MUTATOR GENE FOR UV DAMAGE
XP 变体——紫外线损伤的人类突变基因
  • 批准号:
    6178559
  • 财政年份:
    1998
  • 资助金额:
    $ 33.75万
  • 项目类别:
XP VARIANT--A HUMAN MUTATOR GENE FOR UV DAMAGE
XP 变体——紫外线损伤的人类突变基因
  • 批准号:
    2018664
  • 财政年份:
    1998
  • 资助金额:
    $ 33.75万
  • 项目类别:
The XP Variant: A Human Mutator Gene for UV Damage
XP 变体:导致紫外线损伤的人类突变基因
  • 批准号:
    6908109
  • 财政年份:
    1998
  • 资助金额:
    $ 33.75万
  • 项目类别:
The XP Variant: A Human Mutator Gene for UV Damage
XP 变体:导致紫外线损伤的人类突变基因
  • 批准号:
    6769587
  • 财政年份:
    1998
  • 资助金额:
    $ 33.75万
  • 项目类别:
XP VARIANT--A HUMAN MUTATOR GENE FOR UV DAMAGE
XP 变体——紫外线损伤的人类突变基因
  • 批准号:
    2908982
  • 财政年份:
    1998
  • 资助金额:
    $ 33.75万
  • 项目类别:
The XP Variant: A Human Mutator Gene for UV Damage
XP 变体:导致紫外线损伤的人类突变基因
  • 批准号:
    6327308
  • 财政年份:
    1998
  • 资助金额:
    $ 33.75万
  • 项目类别:

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