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
• 负责人: QUN LU
• 金额: $ 31.5万
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10689335
• 关键词: Acceleration; Acetylcholinesterase Inhibitors; 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; Classification; 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; Protein Inhibition; Proteins; Schizophrenia; Signal Pathway; Signal Transduction; Subutex; Synapses; Tacrine; Testing; Therapeutic; United States National Institutes of Health; Validation; antagonist; aripiprazole; autism spectrum disorder; dementia risk; drug development; endoplasmic reticulum stress; excitotoxicity; human disease; inhibitor; innovation; insight; interdisciplinary approach; mouse genetics; mouse model; neural; neurotoxic; novel; novel therapeutics; presenilin; prevent; protein TDP-43; protein aggregation; protein protein interaction; rab GTP-Binding Proteins; 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 该项目对NIH导演Tra RFA-RM-20-013做出回应，并将检验以下假设。 恢复小GTPase信号传导以修饰阿尔茨海默氏病（AD）和肌萎缩性侧索硬化症（ALS） 与单向靶向相比，发病机理是一种改变游戏的疗法。如果证明了这个新的 创新范式将对其他慢性疾病产生深远和变革性的影响 以及诸如自闭症谱系障碍，精神分裂症和药物成瘾之类的疾病。 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。但是，在许多慢性疾病（例如AD和ALS）中 对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，具有初始激活，然后是抑制作用，反之亦然，以及 在不同大脑区域的激活与抑制作用。简单的单向定位本身可能是主要的 没有成功阻止，逆转甚至修改这种疾病病程的原因 神经退行性疾病。为了克服这一巨大挑战，新的治疗范式必须是 调查。一种方法是恢复体内平衡，而不是完全抑制或激活 影响信号通路。对于AD和ALS，这种方法在很大程度上未经测试，但广泛重要，因为 许多其他复杂疾病还暴露了信号传导的稳态失衡和时空失调 途径，如果使用不当，则使用抑制剂或激活剂无效。 这项TRA项目提案旨在恢复Rho和Rab家族小型GTPase的稳态平衡 信号传导在AD和ALS中在空间上失调。经典的Rho GTPases包括Rhoa， RAC1和CDC42，其中RhoA经常与Rac1和Cdc42相反，以控制蛋白质加工和 贩运和突触重塑。 RAB GTPases还控制着ER应力和蛋白质聚集。 我们的项目将应用创新的双重功能小分子来研究这种对恢复的拮抗作用 他们的体内平衡。我们将确定它们调制对AD和ALS Hallmark蛋白的影响 小鼠模型中的发病机理。如果成功，该项目将提供新颖的一流药物线索，而 新的治疗范式将改变整个AD和ALS药物开发局势及其他地区。 总而言之，我们的建议为建立的变革性影响提供了强有力的理由 AD和ALS中有缺陷的信号传导过程的稳态靶向。具有多机构和多种机构 纪律方法，该项目将导致新颖和重大的见解是否针对稳态 有缺陷的信号的平衡可以修改AD和ALS病程，提供一个开创性的例子 采用相同的方法来对其他慢性和缓慢进展疾病的靶向。