Investigating the roles of a Topoisomerase complex in autophagy and lifespan regulation

研究拓扑异构酶复合物在自噬和寿命调节中的作用

基本信息

  • 批准号:
    10913086
  • 负责人:
  • 金额:
    $ 32.21万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
  • 资助国家:
    美国
  • 起止时间:
  • 项目状态:
    未结题

项目摘要

This new proposal is to investigate how a RNA/DNA dual-activity topoisomerase regulates autophagy and affects lifespan in animal models. Autophagy is an evolutionarily conserved self eating process that is activated when cells and organisms are under starvation3. The optimal autophagic activity is critical to stress survival by removing damaged organelles and recycling necessary proteins and nutrients. Notably, compromised autophagy is a hallmark of aging (Aman et al., Nature Aging, 2021), and has been observed in multiple age related neurodegenerative and autoimmune diseases4,5. In model organisms, reduced autophagy is associated with shortened lifespan, whereas increased autophagy is associated with delayed aging (Aman et al., Nature Aging, 2021). Autophagy is a therapeutic target, as compounds that increase autophagy can improve lifespan and reduce age-associated disease conditions in model organisms. Some of these compounds are being examined in clinical trials (Aman et al., Nature Aging, 2021). Our group has discovered the first DNA/RNA dual activity topoisomerase complex in eucaryotes, Topoisomerase 3 beta (Top3b)-TDRD3. This complex can resolve both DNA and RNA topological complexity. Top3b-Tdrd3 complex can regulate neuronal activity-activated transcription6, mRNA translation and turnover7,8. Notably, the Top3b mutation has been linked to multiple mental disorders including schizophrenia, autism, and intellectual disability6,9,10. Moreover, mouse carrying Top3b mutations exhibits shorter lifespans11. However, the mechanisms underlying how Top3b inactivation can lead to reduced lifespan and neurological disorders remain unclear. One possible mechanism is that Top3b-Tdrd3 may prevent early aging by silencing transposons12,13,the jumping genetic elements that can be a driver of aging and aging associated diseases. Here we propose another possible mechanism-- TOP3B-TDRD3 may prevent premature aging and age associated conditions by promoting autophagy. We will investigate this proposal by using combined expertise of three groups, Wang (Top3b, Drosophila, genomics), DeCabo (starvation, mouse), and Cai (neurological diseases, mouse). It is known that in response to starvation, cellular transcription and translation are both reprogramed (Feng et al., Trends Cell Biol., 2015)(Fullgrabe et al., NRMCB 2014); and expression of many critical autophagy-related genes (ATGs) are activated (Peeters, et al., Autophagy 2019)14. Disruption of activation of autophagy genes can lead to shortened lifespan. Because Top3b-TDRD3 can regulate both transcription and translation, we hypothesize that this complex may also facilitate starvation-induced expression of autophagy genes at either transcription or translation steps. We plan to investigate whether cells or animal models inactivated of TOP3B-TDRD3 exhibit defective expression of autophagy genes, as well as reduced autophagy in three specific aims. Top3b promotes starvation-activated and repressed transcription (Aim 1) We have established the TOP3B-KO and TDRD3-KO HCT116 cell culture system for studies of starvation-induced gene expression and autophagy (Su et al., manuscript in revision). Our RNA-seq shows that many genes are up- or down-regulated in response to starvation, and we named them SAGs (starvation activated genes) and SRGs (starvation repressed genes), respectively. Notably, our ChIP-seq using RNAPII-ser2p antibodies, a transcription elongation marker, revealed that many of those SAGs and SRGs display altered transcription, suggesting that Top3b is critical for starvation induced transcriptional activation and repression. TOP3B-KO alters the transcription of autophagy-associated genes (Aim 1) Our RNA-seq and RNAP2-ser2p ChIP-seq revealed that several autophagy-associated genes show reduced transcription in Top3b-KO HCT116 cells upon starvation. For instance, with a key active autophagy marker, MAP1LC3B transcription is increased by starvation in RNA-seq and RNAPII-ser2p ChIP-seq in WT, but this increase is diminished in Top3b-KO. Western blotting confirmed the reduction of one isoform of this protein. We have also performed lysotracker staining, a common method to detect autophagy; and observed reduced staining in TOP3B-KO cells at 6 hours post starvation. Drosophila exhibits reduced autophagy and shorter lifespan responding to starvation (Aim 2,3) We tested whether autophagy activation in response to starvation is defective in TOP3b-KO Drosophila. Six hours of starvation induced a significant increase of LysoTracker signals in the fat bodies of WT Drosophila 3rd instar larva, however, this activation is nearly completely absent in Top3b-/-, implying that Top3b is necessary for starvation-induced autophagy formation. Notably, we found that the Top3b-/- flies show a significantly shorter lifespan upon starvation vs. WT flies. The data support our hypothesis that Top3b facilitates normal lifespan by promoting autophagy. We have published one paper showing that Top3b-TDRD3 complex promotes transcription starvation-induced genes and autophagy per se in human cancer cells. We also demonstrate that Top3b-KO flies show reduced autophagy (Su et al., NAR 2023).
这个新的提议是研究RNA/DNA双活性拓扑异构酶如何调节自噬并影响动物模型的寿命。自噬是一种进化上保守的自我进食过程,当细胞和生物体处于饥饿状态时,它就会被激活。最佳的自噬活性通过去除受损的细胞器和回收必要的蛋白质和营养物质对应激生存至关重要。值得注意的是,自噬受损是衰老的标志(Aman等人,Nature aging, 2021),在多种与年龄相关的神经退行性疾病和自身免疫性疾病中也有观察到。在模式生物中,自噬减少与寿命缩短有关,而自噬增加与衰老延迟有关(Aman et al., Nature aging, 2021)。自噬是一个治疗靶点,因为增加自噬的化合物可以延长模式生物的寿命并减少与年龄相关的疾病。其中一些化合物正在临床试验中进行检测(Aman等人,Nature Aging, 2021)。

项目成果

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Weidong Wang其他文献

Weidong Wang的其他文献

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{{ truncateString('Weidong Wang', 18)}}的其他基金

Developing proinsulin misfolding inhibitors for beta cell protection and diabetes treatment
开发用于 β 细胞保护和糖尿病治疗的胰岛素原错误折叠抑制剂
  • 批准号:
    10529960
  • 财政年份:
    2022
  • 资助金额:
    $ 32.21万
  • 项目类别:
Developing proinsulin misfolding inhibitors for beta cell protection and diabetes treatment
开发用于 β 细胞保护和糖尿病治疗的胰岛素原错误折叠抑制剂
  • 批准号:
    10665748
  • 财政年份:
    2022
  • 资助金额:
    $ 32.21万
  • 项目类别:
Preclinical Validation of PPARg Acetylation Inhibitors for Diabetes Prevention and Treatment
PPARg 乙酰化抑制剂预防和治疗糖尿病的临床前验证
  • 批准号:
    10580851
  • 财政年份:
    2021
  • 资助金额:
    $ 32.21万
  • 项目类别:
Cytoprotection and the mechanism of action of a natural product Khellin against ER stress
天然产物 Khellin 对抗 ER 应激的细胞保护和作用机制
  • 批准号:
    9974514
  • 财政年份:
    2018
  • 资助金额:
    $ 32.21万
  • 项目类别:
Cytoprotection and the mechanism of action of a natural product Khellin against ER stress
天然产物 Khellin 对抗 ER 应激的细胞保护和作用机制
  • 批准号:
    10285537
  • 财政年份:
    2018
  • 资助金额:
    $ 32.21万
  • 项目类别:
Preclinical Development of Khellin Analogs for Anti-Diabetic Therapy
用于抗糖尿病治疗的 Khellin 类似物的临床前开发
  • 批准号:
    9336063
  • 财政年份:
    2016
  • 资助金额:
    $ 32.21万
  • 项目类别:
Preclinical Development of Khellin Analogs for Anti-Diabetic Therapy
用于抗糖尿病治疗的 Khellin 类似物的临床前开发
  • 批准号:
    9353780
  • 财政年份:
    2016
  • 资助金额:
    $ 32.21万
  • 项目类别:
Identification and Characterization of human Rsc Chromatin-Remodeling Complex
人类 Rsc 染色质重塑复合物的鉴定和表征
  • 批准号:
    6431445
  • 财政年份:
  • 资助金额:
    $ 32.21万
  • 项目类别:
Identification/characterization Complex-Bloom Syndrome
复杂布卢姆综合症的鉴定/表征
  • 批准号:
    7132305
  • 财政年份:
  • 资助金额:
    $ 32.21万
  • 项目类别:
Characterization Complex Involved In Rothmund-Thomson
Rothmund-Thomson 涉及的表征复合体
  • 批准号:
    7132306
  • 财政年份:
  • 资助金额:
    $ 32.21万
  • 项目类别:

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