Prospective Evaluation of Chloride Channel-Targeted Therapy for Alzheimer's disease

氯离子通道靶向治疗阿尔茨海默病的前瞻性评价

• 批准号: 10712797
• 负责人: Ka Ho Leung
• 金额: $ 29.07万
• 依托单位: CLARKSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10712797
• 关键词: Acceleration; Aducanumab; Affect; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease therapy; Amyloid; Antineoplastic Agents; Award; Baby Booms; Brain; Cell Death; Cells; Cessation of life; Chloride Channels; Chlorides; Cholinesterase Inhibitors; Clinical; Clinical Trials; DNA; Dementia; Deposition; Development; Disease; Dose; Drug Approval; Elderly; Eligibility Determination; Evaluation; FDA approved; Family; Fingerprint; Foundations; Galantamine; Generations; Healthcare; Heart Diseases; Homeostasis; Image; Immune response; Impaired cognition; Investigation; Ion Channel; Malignant Neoplasms; Maps; Memantine; NMDA receptor antagonist; Outcome; Parents; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Physiological; Physiology; Play; Prevalence; Problem behavior; Process; Property; Prospective Studies; Psychological Impact; Reporter; Reporting; Research; Role; Signal Pathway; Signal Transduction; Social Impacts; Societies; Stimulator of Interferon Genes; Techniques; Therapeutic; Validation; Work; attenuation; cancer therapy; care burden; channel blockers; disability; donepezil; drug withdrawal; economic impact; effective intervention; human old age (65+); inhibitor; interest; nervous system disorder; pre-clinical research; precision medicine; programs; prospective; reduce symptoms; research and development; response; rivastigmine; success; symptom treatment; targeted treatment

ABSTRACT This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-AG- 22-025. As the most common form of dementia, Alzheimer's disease (AD) is one of the major causes of disability and death among older people. It causes significant economic impacts on society. The prevalence of clinical AD was 11.3% (6.1 million people in US) and this number is predicted to rise to 14 million in 2060. Therefore, therapy that manages or delays AD’s process could significantly reduce the increasing healthcare burden. However, we still lack effective interventions for AD after 40 years of R&D efforts. The FDA’s first disease-modifying, amyloid- targeted therapy, Aduhelm, reduces amyloid deposits in the patient's brain but it has not yet been shown to affect clinical outcomes such as progression of cognitive decline. It indicates that there is an urgent need to have more options for treating Alzheimer’s disease, just as we have many treatments for cancer. cGAS-STING signaling is recognized as a crucial determinant of neuropathophysiology as the elevated signal is observed in Alzheimer's disease or related dementia. However, there are currently no cGAS or STING inhibitors available in clinical stage. Work is underway to develop clinically viable inhibitors with good drug properties. In our parent award, the subcellular chloride reporters and the organellar chemotype fingerprinting techniques could help us to investigate the physiological role of organellar chloride, which is the key to the development of under-studied, chloride channel-targeted therapy. In our preliminary study, we used non- selective chloride channel blockers to induce the whole cell chloride dysregulation. We found that the non- selective chloride channel blockers inhibited the cytosolic-DNA stimulated cGAS-STING signaling in a dose- dependent manner without causing cell death. We hypothesize that cellular/organellar chloride plays an important role in the cGAS-STING signaling pathway. The elevated cGAS-STING signaling in Alzheimer's disease could be inhibited by disturbing the chloride levels via chloride channel targeting. We propose a prospective study, to evaluate the eligibility of chloride channel-targeted therapy for Alzheimer's disease via the attenuation of cGAS-STING pathway. In Aim 1, we will map the chloride homeostasis during the cGAS-STING activation and in Alzheimer's disease. Aim 2 focuses on investigating the role of chloride in cGAS-STING pathway and determine the ability of chloride channel-targeted therapy to suppress the elevated cGAS-STING pathway in Alzheimer's disease. The proposed research integrates organellar chloride imaging, chloride physiology investigation (cGAS-STING), and chloride channel-targeted therapy for Alzheimer’s disease. At the end of the proposed study, we anticipate understanding the role of cellular chloride in cGAS-STING pathway and prospectively evaluate the eligibility of chloride channel-targeted therapy to dampen the elevated cGAS- STING signaling in Alzheimer's disease. It will lay the foundation for chloride physiology and prospective validation of chloride channel-targeted therapy for Alzheimer's disease and related neurological disorders.

摘要 本申请是对被确认为NOT-AG-的特别利益通知(NOSI)的回应。 22-025。作为最常见的痴呆症，阿尔茨海默病(AD)是导致残疾的主要原因之一 以及老年人的死亡。它对社会造成了重大的经济影响。临床阿尔茨海默病的患病率 是11.3%(美国有610万人)，这一数字预计到2060年将上升到1400万。因此，治疗 管理或推迟AD的过程可以显著减轻日益增加的医疗负担。然而，我们 经过40年的研发努力，AD仍然缺乏有效的干预措施。FDA的第一个治疗疾病的淀粉样蛋白- 靶向治疗Aduhelm减少了患者大脑中淀粉样蛋白的沉积，但尚未显示出影响 临床结果，如认知功能减退的进行性。它表明，迫切需要有 治疗阿尔茨海默病有更多的选择，就像我们有许多治疗癌症的方法一样。CGAS-STING 信号被认为是神经病理生理学的关键决定因素，因为在 阿尔茨海默病或相关痴呆症。然而，目前还没有可用的cGAS或刺痛抑制剂 临床阶段。目前正在开发具有良好药物性能的临床可行的抑制剂。 在我们的家长奖中，亚细胞氯化物报告和细胞器化学指纹图谱 技术可以帮助我们研究有机氯的生理作用，这是 正在研究中的氯离子通道靶向治疗的发展。在我们的初步研究中，我们使用了非 选择性氯离子通道阻滞剂可诱导全细胞氯离子失调。我们发现非- 选择性氯通道阻滞剂在一定剂量范围内抑制胞浆DNA刺激的cGAS-STING信号转导 依赖方式，不会导致细胞死亡。我们假设细胞/细胞器中的氯化物在 在cGAS-STING信号通路中发挥重要作用。阿尔茨海默病患者cGAS刺痛信号的升高 通过氯通道靶向干扰氯水平，可以抑制疾病的发生。我们提出了一个 前瞻性研究，评估氯通道靶向治疗阿尔茨海默病的适合性。 CGAS-STING途径的减弱。在目标1中，我们将绘制cGAS刺痛期间的氯离子动态图 在阿尔茨海默氏症中也是如此。目的2重点研究氯离子在cGAS刺痛中的作用 氯离子通道靶向治疗抑制升高的cGAS-刺激物的能力 阿尔茨海默病中的通路。拟议的研究将有机氯化物成像、氯化物 阿尔茨海默病的生理学研究(cGAS-STING)和氯离子通道靶向治疗。在 在拟议的研究结束时，我们期望了解细胞氯在cGAS-STING途径中的作用 并前瞻性评估氯通道靶向治疗以抑制升高的cGAS的适合性。 阿尔茨海默病中的刺痛信号。为氯离子生理学和应用前景奠定了基础。 氯离子通道靶向治疗阿尔茨海默病及相关神经疾病的有效性。