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The Role of LEM Domain Proteins in Nuclear Function

The Role of LEM Domain Proteins in Nuclear Function
LEM 结构域蛋白在核功能中的作用
批准号:
10175883
负责人:
PAMELA K. GEYER
金额:
$14.81万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2010
资助国家:
美国
项目状态:
已结题
起止时间:
2010-06-01 至 2023-06-30

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中文摘要
翻译
项目摘要 人类核纤层蛋白病是由编码核纤层蛋白(NL)的基因突变引起的。 一个统一的疾病模型表明,失去组织稳态是由于未能维持 成体干细胞尽管已经鉴定了负责核纤层蛋白病的NL蛋白, 目前尚不清楚这些蛋白质如何维持健康的干细胞群, 组织内稳态保守的NL家族LEM-结构域(LEM-D)蛋白发挥关键作用, 在建立核结构和NL中的作用。LEM-D蛋白结合自身整合屏障 因子(BAF),一种双链DNA和组蛋白结合蛋白。我们研究果蝇 LEM-D家族,重点关注Otefin,一种成年生殖系存活所需的LEM-D蛋白 干细胞(GSC)。otefin突变GSC携带NL和染色质的结构畸形 与核纤层病变细胞共享的变化。我的实验室发现这些变异的GSC 由于激活了一种新的检查点途径,该途径使用两种DNA损伤反应 (DDR)激酶,ATR和检查点激酶2(Chk 2)。虽然otefin突变体GSC携带DNA 损伤,损伤累积依赖于Chk 2,表明DNA损伤导致 检查点激活。基于这些和其他数据,我们假设NL变形 负责ATR和Chk 2的激活,这一预测得到了新证据的支持, ATR是细胞成分结构变形的全局传感器。在这份提案中,两名 提出了目标。在目的1中,我们将定义otefin中ATR/Chk 2激活的机制 突变的GSC。在目标2中,我们定义了参与GSC死亡的Chk 2依赖性途径。核 形状改变是核纤层蛋白病和早衰综合征的共同特征。我们 预测NL检查点的激活可能有助于干细胞维持的丢失, 这些疾病。
英文摘要
Project Summary Human laminopathies are caused by mutations in genes encoding nuclear lamina (NL) proteins. A unifying disease model suggests that lost tissue homeostasis is due to a failure to maintain adult stem cells. Although NL proteins responsible for laminopathies have been identified, it remains unclear how these proteins maintain healthy stem cell populations and promote tissue homeostasis. The conserved NL family of LEM-domain (LEM-D) proteins play a critical role in building nuclear structure and the NL. LEM-D proteins bind Barrier-to-Autointegration Factor (BAF), a double stranded DNA and histone binding protein. We investigate the Drosophila LEM-D family, focusing on Otefin, a LEM-D protein that is required for survival of adult germline stem cells (GSCs). The otefin mutant GSCs carry structural deformities of the NL and chromatin changes that are shared with laminopathic cells. My lab discovered that these mutant GSCs die because of activation of a novel checkpoint pathway that uses two DNA damage response (DDR) kinases, ATR and Checkpoint kinase 2 (Chk2). Although otefin mutant GSCs carry DNA damage, damage accumulation depends upon Chk2, demonstrating that DNA damage results from checkpoint activation. Based on these and other data, we hypothesize that NL deformation is responsible for activation of ATR and Chk2, a prediction supported by emerging evidence that ATR is a global sensor of structural deformities of cellular components. In this proposal, two Aims are proposed. In Aim 1, we will define the mechanism of ATR/Chk2 activation in otefin mutant GSCs. In Aim 2, we define Chk2-dependent pathways involved in GSC death. Nuclear shape changes are shared features of laminopathies and premature aging syndromes. We predict that activation of the NL checkpoint might contribute to lost stem cell maintenance in these diseases.
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Expanding program evaluation capacity and enhancing training programs through alumni perspectives
  • 批准号:
    10592969
  • 项目类别:
  • 资助金额:
    $8.64万
  • 财政年份:
    2021
  • 负责人:
    PAMELA K. GEYER
  • 依托单位:
Aging and the nuclear lamina in mitotic stem cells
  • 批准号:
    10209608
  • 项目类别:
  • 资助金额:
    $23.18万
  • 财政年份:
    2021
  • 负责人:
    PAMELA K. GEYER
  • 依托单位:
Aging and the nuclear lamina in mitotic stem cells
  • 批准号:
    10380783
  • 项目类别:
  • 资助金额:
    $19.31万
  • 财政年份:
    2021
  • 负责人:
    PAMELA K. GEYER
  • 依托单位:
Medical Scientist Training Program
  • 批准号:
    10088081
  • 项目类别:
  • 资助金额:
    $96.77万
  • 财政年份:
    2021
  • 负责人:
    PAMELA K. GEYER
  • 依托单位:
海外基金