Homeostatic Reset as a New Therapeutic Paradigm for Slow Progression Diseases

稳态重置作为缓慢进展疾病的新治疗范式

基本信息

  • 批准号:
    10796004
  • 负责人:
  • 金额:
    --
  • 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:
    2021-09-15 至 2023-12-31
  • 项目状态:
    已结题

项目摘要

Project Summary This project responds to NIH Directors TRA RFA-RM-20-013 and will test the hypothesis that homeostatic restoration of small GTPase signaling to modify Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS) pathogenesis is a game-changing therapeutic approach compared to unidirectional targeting. If proven, this new and innovative paradigm will have far-reaching and transformative impact for targeting other chronic diseases and disorders such as autism spectrum disorder, schizophrenia, and drug addiction. The predominant and conventional therapeutic strategies in treating human diseases are unidirectionally inhibiting or stimulating affected biological processes. However, in many chronic diseases such as AD and ALS, complete inhibition or activation of the affected signaling events may themselves promote diseases. Disease progression can also be spatiotemporal, with initial activation followed by inhibition or vice versa, as well as activation versus inhibition at different brain regions. Thus, simple unidirectional targeting may itself be a major reason that no drugs have successfully prevented, reversed or even modified the disease course for such neurodegenerative disorders. To overcome this formidable challenge, new therapeutic paradigms must be investigated. One approach is to restore homeostatic balance instead of completely inhibiting or activating the affected signaling pathways. This approach is largely untested for AD and ALS but is broadly significant because many other complex diseases also exhibit homeostatic imbalance and spatiotemporal dysregulation of signaling pathways, making the use of inhibitors or activators ineffective if used inappropriately. This TRA project proposes to restore the homeostatic balance of Rho and Rab family small GTPase signaling, which is spatiotemporally dysregulated in AD and ALS. The classical Rho GTPases include RhoA, Rac1, and Cdc42, in which RhoA often acts in opposition to Rac1 and Cdc42 to control protein processing and trafficking as well as synaptic remodeling. Rab GTPases additionally control ER stress and protein aggregation. Our project will apply innovative dual function small molecules to investigate this antagonism for restoring their homeostatic balance. We will determine the effects of their modulation on AD and ALS hallmark proteins and pathogenesis in mouse models. If successful, this project will deliver novel first-in-class drug leads, and the new therapeutic paradigm will transform the entire AD and ALS drug development landscape and beyond. In summary, our proposal provides a strong rationale for the transformative impact of establishing homeostatic targeting at defective signaling processes in AD and ALS. With a multi-institution and multi- disciplinary approach, this project will lead to novel and significant insights into whether targeting homeostatic balances of defective signaling can modify AD and ALS disease course, providing a pioneering example of applying the same approach for future targeting of other chronic and slow progression diseases.
项目摘要 该项目回应了NIH主任TRA RFA-RM-20-013,并将测试内环境平衡的假设 修复小GTP酶信号以修饰阿尔茨海默病(AD)和肌萎缩侧索硬化(ALS) 与单向靶向相比,病机是一种改变游戏规则的治疗方法。如果得到证实,这一新的 而创新的范式将对其他慢性病产生深远和变革性的影响 以及自闭症谱系障碍、精神分裂症和毒瘾等障碍。 治疗人类疾病的主要和常规治疗策略是单向的。 抑制或刺激受影响的生物过程。然而,在许多慢性病中,如阿尔茨海默病和肌萎缩侧索硬化, 完全抑制或激活受影响的信号事件本身可能会促进疾病。疾病 进程也可以是时空的,先激活后抑制,反之亦然 不同脑区的激活与抑制。因此,简单的单向定向本身可能是一个主要的 没有药物能够成功地预防、逆转甚至改变这种疾病的病程 神经退行性疾病。为了克服这一艰巨的挑战,新的治疗范例必须 调查过了。一种方法是恢复动态平衡,而不是完全抑制或激活 受影响的信号通路。这种方法在很大程度上没有在AD和ALS中进行测试,但广泛意义重大,因为 许多其他复杂疾病也表现出体内平衡失衡和信号的时空失调。 途径,使使用抑制剂或激活剂无效,如果使用不当。 这个TRA项目建议恢复Rho和Rab家族小GTP酶的动态平衡 在阿尔茨海默病和肌萎缩侧索硬化症中,信号在时空上是失调的。经典的Rho GTP酶包括RhoA, Rac1和cdc42,其中RhoA经常与rac1和cd42相反,以控制蛋白质的加工和 运输以及突触重塑。Rab GTP酶还控制内质网应激和蛋白质聚集。 我们的项目将应用创新的双功能小分子来研究这种拮抗作用以恢复 他们的动态平衡。我们将确定它们对AD和ALS标志蛋白的调节作用 以及在小鼠模型中的发病机制。如果成功,这个项目将提供新的一流药物线索,并且 新的治疗模式将改变整个AD和ALS药物开发格局,甚至更远。 总而言之,我们的建议为建立 动态平衡靶向AD和ALS中有缺陷的信号过程。多机构、多机构、多领域 纪律方法,这个项目将导致对是否以动态平衡为目标的新的和重要的见解 有缺陷的信号平衡可以改变AD和ALS的病程,提供了一个先例 将同样的方法应用于其他慢性和慢性进展疾病的未来目标。

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)
RhoA-LIMK Signaling Axis Reveals Rostral-Caudal Plane and Spatial Dysregulation in the Brain of Alzheimer's Disease Mouse Models.
  • DOI:
    10.3233/jad-230408
  • 发表时间:
    2023-09
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Shayan Nik Akhtar;Quanlong Lu
  • 通讯作者:
    Shayan Nik Akhtar;Quanlong Lu
Trans-Compartmental Regulation of Tight Junction Barrier Function.
  • DOI:
    10.1080/21688370.2022.2133880
  • 发表时间:
    2023-10-02
  • 期刊:
  • 影响因子:
    3.1
  • 作者:
    Naser, Amna N.;Lu, Qun;Chen, Yan-Hua
  • 通讯作者:
    Chen, Yan-Hua
Nanoarchitecture and molecular interactions of epithelial cell junction proteins revealed by super-resolution microscopy.
TRPV4: En RhoA To a Cure?
  • DOI:
    10.1002/bies.202200071
  • 发表时间:
    2022-06
  • 期刊:
  • 影响因子:
    4
  • 作者:
    Lu, Qun;Chen, Yan-Hua
  • 通讯作者:
    Chen, Yan-Hua
Crosstalk between the Rho and Rab family of small GTPases in neurodegenerative disorders.
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QUN LU其他文献

QUN LU的其他文献

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{{ truncateString('QUN LU', 18)}}的其他基金

Homeostatic Reset as a New Therapeutic Paradigm for Slow Progression Diseases
稳态重置作为缓慢进展疾病的新治疗范式
  • 批准号:
    10273546
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
Homeostatic Reset as a New Therapeutic Paradigm for Slow Progression Diseases
稳态重置作为缓慢进展疾病的新治疗范式
  • 批准号:
    10689335
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
Homeostatic Reset as a New Therapeutic Paradigm for Slow Progression Diseases
稳态重置作为缓慢进展疾病的新治疗范式
  • 批准号:
    10488273
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
Rho GTPases and Neuroprotection Model in Cancer Therapy
Rho GTPases 和癌症治疗中的神经保护模型
  • 批准号:
    8232481
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:
Rho GTPases and Neuroprotection Model in Cancer Therapy
Rho GTPases 和癌症治疗中的神经保护模型
  • 批准号:
    8769217
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:
delta-Catenin and Cell-Cell Adhesion in Prostate Cancer
前列腺癌中的 δ-连环蛋白和细胞间粘附
  • 批准号:
    7035153
  • 财政年份:
    2006
  • 资助金额:
    --
  • 项目类别:
delta-Catenin and Cell-Cell Adhesion in Prostate Cancer
前列腺癌中的 δ-连环蛋白和细胞间粘附
  • 批准号:
    7186628
  • 财政年份:
    2006
  • 资助金额:
    --
  • 项目类别:
delta-Catenin and Cell-Cell Adhesion in Prostate Cancer
前列腺癌中的 δ-连环蛋白和细胞间粘附
  • 批准号:
    8068992
  • 财政年份:
    2006
  • 资助金额:
    --
  • 项目类别:
delta-Catenin and Cell-Cell Adhesion in Prostate Cancer
前列腺癌中的 δ-连环蛋白和细胞间粘附
  • 批准号:
    7554661
  • 财政年份:
    2006
  • 资助金额:
    --
  • 项目类别:
delta-Catenin and Cell-Cell Adhesion in Prostate Cancer
前列腺癌中的 δ-连环蛋白和细胞间粘附
  • 批准号:
    7345429
  • 财政年份:
    2006
  • 资助金额:
    --
  • 项目类别:
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