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 该申请是根据特殊利益通知（NOSI）提交的 22-025是痴呆症的最常见形式，阿尔茨海默氏病（AD）是残疾人 和老年人的死亡。 为11.3％（美国610万人），预计该数字在2060年将增加到1400万。 管理或延迟广告的过程可能会大大减轻我们的医疗保健负担 在40年的R＆D预付款后，仍然缺乏对AD的有效干预措施。 靶向疗法Aduhelm，减少了患者大脑中的淀粉样蛋白沉积物，但受到影响以影响 临床结果，例如认知能力下降。 我们有许多治疗方法的方法来治疗阿尔茨海默氏病 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 阿尔茨海默氏病或​​相关痴呆症。 在临床阶段，正在开发具有良好药物特性的临床可行抑制剂。 在我们的父母奖中，细胞亚细胞氯化物记者和细胞器化学型指纹印刷 技术可以帮助我们研究Oranlar氯化物的生理作用，这是 在我们的初步研究中，研究不足的氯化物通道的疗法。 选择性氯化物通道阻滞剂诱导整个细胞氯化物失调。 选择性氯化物通道阻滞剂抑制了剂量 - 我们假设细胞/细胞器氯化物不引起细胞死亡的方式 CGAS刺激信号通路中的重要作用。 通过氯化物通道的靶向，可以抑制疾病 前瞻性研究，以评估通过茶TE TE TE INFORAPYIMER病的含氯化物通道靶向治疗的资格 CGAS刺激途径的衰减。 激活和阿尔茨海默氏病。 途径并确定针对氯化物通道的治疗能力抑制高架CGAS的能力 阿尔茨海默氏病的途径。 生理研究（CGAS-STING）和Cloride渠道对Therzheimer疾病的态度 支撑研究的结尾，我们预计了解窖藏在CGAS刺道途径中的作用 并前瞻性评估氯化物通道靶向治疗的资格升高的CGA- 阿尔茨海默氏病中的刺激信号会为氯化物奠定基础 对阿尔茨海默氏病和相关神经病学疾病的氯化物通道验证治疗的验证。