Cell-Cell Interactions In Alzheimer's disease and related dementias

阿尔茨海默病和相关痴呆症中的细胞间相互作用

基本信息

  • 批准号:
    10711899
  • 负责人:
  • 金额:
    $ 31.48万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-08-01 至 2026-06-30
  • 项目状态:
    未结题

项目摘要

Alzheimer’s disease (hereafter, AD), a progressive neurodegenerative disorder, is fatal with no effective cure to date. AD manifests as gradual decline in cognitive functions of learning and memory due to selective atrophy of the hippocampus and frontal cerebral cortex in the brain. The neurodegeneration associated with AD also coincides with accumulation of amyloid-beta 42 (Aß42) plaques. The accumulation of Aβ42 plaques and NFTs in AD triggers progressive neurodegeneration across brain regions. It is not clear how cellular changes contribute to the progression from an initial asymptomatic period into a phase of stark cognitive decline. The molecular genetic mechanisms underlying the Aβ42 mediated neurodegeneration are not fully understood. Many strategies including model organisms have been devised. Drosophila melanogaster, fruit fly, with a large array of genetic tools, and similar genetic makeup to humans is an excellent model for human diseases including AD. Drosophila can be used for high throughput genome wide- and for therapeutic compound screens. We have established a transgenic fly model where we misexpress high levels of human Aß42 polypeptides in the retinal neurons of the eye, which exhibits AD like neuropathology of progressive neuronal death. This stable transgenic line exhibits Aß42 mediated cell death in nearly 100% flies at 29oC. Our goal is to employ our Drosophila eye model to identify (a) downstream target genes and (b) reporters/ sensors to detect AD, and (c) look for complex interaction between Aß42-producing and wild-type neurons during Alzheimer’s neuropathology. We identified the highly conserved growth regulatory Wingless (Wg)/Wnt signaling pathway as the dominant modifier of Aß42-mediated neurodegeneration. The first aim is to determine the involvement of Wg signaling in Aβ42-mediated neurodegeneration. Wg signaling has been studied in cell survival and differentiation, and not in neurodegeneration. We will test if modulation of the Wg signaling pathway can modulate Aβ42-mediated neurodegeneration. We will test if the reporters/sensors of the Wg pathway can be used to detect Aß42-mediated neurodegeneration. In the second aim, we will determine if Wg pathway activation triggers neurodegeneration in wild-type cells or in Aβ42-expressing cells. We will use our two clone systems to determine if there is any cross-talk between the wild-type neurons and Aß42 producing neurons. Our hypothesis is that aberrant Wg signaling might trigger cell death in wild-type neurons. These proposed studies aim to provide a useful blueprint to study cross-talk between cell populations in neurodegenerative disease. This may potentially identify new biomarkers that can be differentially regulated between Aβ42-expressing and WT neurons. Better understanding of the local context of cell death in progressive neurodegenerative disease is a vital next step in developing new interventions to slow or halt disease progression.
阿尔茨海默病(以下简称 AD)是一种进行性神经退行性疾病,具有致命性,目前尚无有效治疗方法 治愈至今。 AD表现为学习和记忆等认知功能逐渐下降。 大脑中海马体和额叶大脑皮层的选择性萎缩。神经退行性变 与 AD 相关的也与淀粉样蛋白 β 42 (Aß42) 斑块的积累同时发生。积累 AD 中的 Aβ42 斑块和 NFT 会引发整个大脑区域的进行性神经退行性变。它不是 清楚细胞变化如何促进从最初的无症状期到无症状期的进展 认知能力明显下降。 Aβ42介导的分子遗传机制 神经退行性疾病尚未完全了解。包括模式生物在内的许多策略已被 设计的。果蝇,果蝇,具有大量遗传工具和相似的基因组成 对人类来说是包括 AD 在内的人类疾病的优秀模型。果蝇可用于高 全基因组通量和治疗化合物筛选。我们已经建立了转基因果蝇 我们在眼睛视网膜神经元中错误表达高水平的人类 Aß42 多肽的模型, 其表现出类似 AD 的进行性神经元死亡的神经病理学。该稳定的转基因品系表现出 29oC 时,Aß42 介导近 100% 果蝇的细胞死亡。我们的目标是利用果蝇眼睛模型 识别 (a) 下游目标基因和 (b) 报告基因/传感器以检测 AD,以及 (c) 寻找复杂的 阿尔茨海默病神经病理学过程中产生 Aß42 的神经元和野生型神经元之间的相互作用。我们 确定高度保守的生长调节 Wingless (Wg)/Wnt 信号通路是主要的 Aß42 介导的神经变性的修饰剂。第一个目标是确定 Wg 的参与 Aβ42 介导的神经变性中的信号传导。 Wg 信号传导已在细胞存活和 分化,而不是神经变性。我们将测试 Wg 信号通路的调节是否可以 调节 Aβ42 介导的神经变性。我们将测试 Wg 途径的报告基因/传感器是否可以 用于检测 Aß42 介导的神经变性。在第二个目标中,我们将确定 Wg 通路是否 激活会引发野生型细胞或表达 Aβ42 的细胞的神经变性。我们将使用我们的两个 克隆系统以确定野生型神经元和产生 Aß42 的神经元之间是否存在任何串扰 神经元。我们的假设是,异常的 Wg 信号传导可能会引发野生型神经元的细胞死亡。这些 拟议的研究旨在提供一个有用的蓝图来研究细胞群之间的串扰 神经退行性疾病。这可能会识别出可以差异化的新生物标志物 在表达 Aβ42 的神经元和 WT 神经元之间进行调节。更好地了解细胞的局部环境 进行性神经退行性疾病的死亡是制定新干预措施以减缓进展的重要下一步 或阻止疾病进展。

项目成果

期刊论文数量(12)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Opposing interactions between homothorax and Lobe define the ventral eye margin of Drosophila eye.
  • DOI:
    10.1016/j.ydbio.2011.08.017
  • 发表时间:
    2011-11-15
  • 期刊:
  • 影响因子:
    2.7
  • 作者:
    Singh A;Tare M;Kango-Singh M;Son WS;Cho KO;Choi KW
  • 通讯作者:
    Choi KW
N-Acetyltransferase 9 ameliorates Aβ42-mediated neurodegeneration in the Drosophila eye.
  • DOI:
    10.1038/s41419-023-05973-z
  • 发表时间:
    2023-07-28
  • 期刊:
  • 影响因子:
    9
  • 作者:
    Deshpande, Prajakta;Chimata, Anuradha Venkatakrishnan;Snider, Emily;Singh, Aditi;Kango-Singh, Madhuri;Singh, Amit
  • 通讯作者:
    Singh, Amit
miR-277 targets the proapoptotic gene-hid to ameliorate Aβ42-mediated neurodegeneration in Alzheimer's model.
  • DOI:
    10.1038/s41419-023-06361-3
  • 发表时间:
    2024-01-18
  • 期刊:
  • 影响因子:
    9
  • 作者:
    Deshpande, Prajakta;Chen, Chao-Yi;Chimata, Anuradha Venkatakrishnan;Li, Jian-Chiuan;Sarkar, Ankita;Yeates, Catherine;Chen, Chun-Hong;Kango-Singh, Madhuri;Singh, Amit
  • 通讯作者:
    Singh, Amit
Unbiased automated quantitation of ROS signals in live retinal neurons of Drosophila using Fiji/ImageJ.
  • DOI:
    10.2144/btn-2021-0006
  • 发表时间:
    2021-08
  • 期刊:
  • 影响因子:
    2.7
  • 作者:
  • 通讯作者:
Signaling interactions among neurons impact cell fitness and death in Alzheimer's disease.
  • DOI:
    10.4103/1673-5374.354516
  • 发表时间:
    2023-04
  • 期刊:
  • 影响因子:
    6.1
  • 作者:
    Yeates C;Deshpande P;Kango-Singh M;Singh A
  • 通讯作者:
    Singh A
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Madhuri Kango-Singh其他文献

Madhuri Kango-Singh的其他文献

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{{ truncateString('Madhuri Kango-Singh', 18)}}的其他基金

Genetic Basis of Dorso-Ventral Patterning in the Drosophila Eye
果蝇眼背腹模式的遗传基础
  • 批准号:
    10652488
  • 财政年份:
    2021
  • 资助金额:
    $ 31.48万
  • 项目类别:
Genetic Basis of Dorso-Ventral Patterning in the Drosophila Eye
果蝇眼背腹模式的遗传基础
  • 批准号:
    10279832
  • 财政年份:
    2021
  • 资助金额:
    $ 31.48万
  • 项目类别:
Genetic Basis of Dorso-Ventral Patterning in the Drosophila Eye
果蝇眼背腹模式的遗传基础
  • 批准号:
    10459551
  • 财政年份:
    2021
  • 资助金额:
    $ 31.48万
  • 项目类别:
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