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.

抽象的 本申请是为了响应被标识为 NOT-AG- 的特殊利益通知 (NOSI) 而提交的 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。 临床 AD 的流行对社会造成重大经济影响。 为 11.3%（美国有 610 万人），预计到 2060 年这一数字将增至 1400 万。因此，治疗 管理或延迟 AD 过程可以显着减轻日益增加的医疗负担。 经过 40 年的研发努力，AD 仍然缺乏有效的干预措施。 靶向治疗 Aduhelm 可减少患者大脑中的淀粉样蛋白沉积，但尚未被证明会影响 临床结果，例如认知能力下降的进展，表明迫切需要进行治疗。 治疗阿尔茨海默病的更多选择，就像我们有许多癌症治疗方法一样。 信号传导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目前尚无可用的 cGAS 或 STING 抑制剂。 正在临床阶段开发具有良好药物特性的临床上可行的抑制剂。 在我们的家长奖中，亚细胞氯化物的产生和细胞器化学型指纹识别 技术可以帮助我们研究细胞器氯化物的生理作用，这是细胞器氯化物的关键 尚未研究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-氯离子通道靶向疗法。 我们发现选择性氯离子通道阻滞剂会诱导全细胞氯离子失调。 选择性氯离子通道阻滞剂在一定剂量下抑制细胞质 DNA 刺激的 cGAS-STING 信号传导 我们认为细胞/细胞器的氯化物起着重要作用。 cGAS-STING 信号通路在阿尔茨海默病中升高的 cGAS-STING 信号通路中发挥重要作用。 我们提出了一种通过氯离子通道靶向干扰氯离子水平来抑制疾病的方法。 前瞻性研究，通过以下方法评估氯离子通道靶向治疗阿尔茨海默病的资格 cGAS-STING 途径的衰减 在目标 1 中，我们将绘制 cGAS-STING 期间的氯离子稳态图。 目标 2 重点研究氯化物在 cGAS-STING 中的作用。 途径并确定氯离子通道靶向治疗抑制 cGAS-STING 升高的能力 拟议的研究整合了细胞器氯化物成像、氯化物。 生理学研究（cGAS-STING）和针对阿尔茨海默病的氯离子通道靶向治疗。 在拟议的研究结束时，我们期望了解细胞氯在 cGAS-STING 通路中的作用 并前瞻性评估氯离子通道靶向治疗抑制 cGAS 升高的资格 阿尔茨海默病中的 STING 信号传导将为氯化物生理学和前瞻性奠定基础。 验证氯离子通道靶向治疗阿尔茨海默病和相关神经系统疾病。