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
• 负责人: QUN LU
• 金额: $ 62.71万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10273546
• 关键词: Acetylcholine; Affect; Agonist; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyotrophic Lateral Sclerosis; Antidepressive Agents; Apolipoprotein E; Area; Biological Process; Brain Diseases; Brain region; Buprenorphine; C9ORF72; Cellular biology; Chronic; Chronic Disease; Clinical; Complex; Computer Models; Disease; Disease Progression; Down Syndrome; Drug Addiction; Equilibrium; Event; Excitatory Amino Acid Antagonists; Exhibits; FDA approved; Family; Future; Generations; Genes; Goals; Human; Institution; Learning; Medicine; Memantine; Memory; Monomeric GTP-Binding Proteins; Mus; Neurodegenerative Disorders; Neurosciences; Pain; Pathogenesis; Pesticides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Process; Proteins; Schizophrenia; Signal Pathway; Signal Transduction; Subutex; Synapses; Tacrine; Testing; Therapeutic; United States National Institutes of Health; Validation; aripiprazole; autism spectrum disorder; dementia risk; drug development; endoplasmic reticulum stress; esterase inhibitor; excitotoxicity; human disease; inhibitor/antagonist; innovation; insight; interdisciplinary approach; mouse genetics; mouse model; neurotoxic; novel; novel therapeutics; presenilin; prevent; protein TDP-43; protein aggregation; protein protein interaction; rab GTP-Binding Proteins; relating to nervous system; restoration; rho; rho GTP-Binding Proteins; small molecule; spatiotemporal; superoxide dismutase 1; tau Proteins; trafficking

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 该项目响应NIH主任TRA RFA-RM-20-013，并将测试稳态的假设， 恢复小GT3信号传导以改变阿尔茨海默病（AD）和肌萎缩侧索硬化（ALS） 与单向靶向相比，发病机制是一种改变游戏规则的治疗方法。如果得到证实， 创新的模式将对其他慢性病产生深远的变革性影响 以及诸如自闭症谱系障碍、精神分裂症和药物成瘾的障碍。 治疗人类疾病的主要和常规的治疗策略是单向的 抑制或刺激受影响的生物过程。然而，在许多慢性疾病如AD和ALS中， 受影响的信号事件的完全抑制或激活本身可能促进疾病。疾病 进展也可以是时空的，初始激活后是抑制，反之亦然，以及 激活与抑制在不同的大脑区域。因此，简单的单向目标本身可能是一个主要的 原因是没有药物成功地预防，逆转或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，新的治疗模式必须 研究了一种方法是恢复稳态平衡，而不是完全抑制或激活 影响信号通路。这种方法在很大程度上没有经过AD和ALS的测试，但具有广泛的意义，因为 许多其他复杂疾病也表现出稳态失衡和信号传导的时空失调 途径，使使用抑制剂或激活剂无效，如果使用不当。 本TRA项目旨在恢复Rho和Rab家族小GTdR的稳态平衡， 信号传导，其在AD和ALS中时空失调。经典的Rho GTP酶包括RhoA， Rac 1和Cdc 42，其中RhoA通常与Rac 1和Cdc 42相反地起作用以控制蛋白质加工， 以及突触重塑。Rab GTP酶另外控制ER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， 他们的自我平衡我们将确定它们对AD和ALS标志蛋白的调节作用， 和发病机制。如果成功，该项目将提供新型的一流药物， 新的治疗范式将改变整个AD和ALS药物开发格局及其他领域。 总之，我们的建议为建立一个具有变革性影响的 针对AD和ALS中有缺陷的信号传导过程的稳态靶向。一个多机构和多- 学科的方法，该项目将导致新的和重要的见解，无论是针对稳态 缺陷信号的平衡可以改变AD和ALS疾病的进程，提供了一个开创性的例子， 将同样的方法应用于其他慢性和缓慢进展疾病的未来靶向。