Blocking TGF-Beta immune signaling as a therapeutic target for Alzheimer's diseas

阻断 TGF-β 免疫信号作为阿尔茨海默病的治疗靶点

• 批准号: 7223795
• 负责人: TERRENCE C TOWN
• 金额: $ 9万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7223795
• 关键词: Adopted; Alzheimer like pathology; Alzheimer' s Disease; American; Amyloid; Animals; Antibodies; Award; Behavioral; Blocking Antibodies; Brain; Brain Pathology; CD11 Antigens; Cells; Data; Deposition; Development Plans; Disease; Doctor of Philosophy; Dominant-Negative Mutation; Elderly; Encephalitis; Environment; Goals; ITGAX gene; Immune; Immunology; Impairment; Inflammatory Response; Laboratories; Lesion; Measures; Mentors; Mentorship; Microglia; Mus; Neurosciences; Pathology; Peptides; Phagocytosis; Phase; Positioning Attribute; Postdoctoral Fellow; Proteins; Research; Route; Scientist; Signal Transduction; Tetracycline; Tetracyclines; Tg2576; Therapeutic; Training; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Transgenes; Transgenic Mice; Transgenic Organisms; United States; Work; aged; career; cell type; chemokine; cohort; cytokine; intraperitoneal; macrophage; mouse model; neuroimmunology; novel therapeutics; receptor; research study; response; therapeutic target; transgene expression

DESCRIPTION (provided by applicant): The overriding aim of this proposal is to investigate the therapeutic potential of blocking transforming growth factor-beta (TGF-beta) signaling for Alzheimer's disease. Terrence Town, Ph.D. is currently an NRSA/NIA post-doctoral fellow with the immediate goal of completing an additional year of mentored research. Dr. Town has been working at the interface of the immunology and neuroscience fields, and his current environment in Dr. Flavell's laboratory with co-sponsorship from Dr. Rakic positions him in the ideal environment within which to complete the mentored phase of the proposed project. Dr. Town's long-term goals inclulde establishing himself as an independent scientist in a tenure-track academic position, and contributing to understanding neuroimmune aspects of Alzheimer's disease, with the hope of finding novel therapeutic targets for this devastating illness. Dr. Town's career development plan includes receiving training and mentorship in neuroimmunology. Following the proposed one year period of mentored research, Dr. Town plans to make the transition to independence with the assistance of the proposed award. For the mentored period, Dr. Town proposes to evaluate Alzheimer-like pathology in a transgenic mouse model of the disease crossed with a transgenic mouse that has blocked TGF-beta signaling in innate immune cells. The proposed work during the mentored phase builds heavily on preliminary data that show that one such crossed mouse has mitigation of Alzheimer-like pathology. For the independent phase, Dr. Town will 1) investigate the potential cellular mechanism underlying reduced Alzheimer pathology in crossed mice, 2) adopt a pharmacotherapeutic approach by treating Alzheimer transgenic mice with TGF-beta receptor blocking antibody, and 3) conduct another mouse crossing experiment to determine if blocking TGF-beta signaling on innate immune cells mitigates Alzheimer-like pathology during its initial establishment or after active lesions are formed. RELEVANCE: Alzheimer's disease is the most common dementing illness in the United States, and it is estimated that over 3 million Americans over the age of 65 have the disease. This project aims to uncover a new avenue for the treatment of Alzheimer's disease by blocking a protein that has been shown to be involved in the pathological changes of the disease, specifically the brain's inflammatory response.

描述（由申请人提供）：本提案的首要目的是研究阻断转化生长因子-β（TGF-β）信号传导治疗阿尔茨海默病的治疗潜力。特伦斯镇，博士目前是NRSA/NIA博士后研究员，其直接目标是完成额外一年的指导研究。Town博士一直在免疫学和神经科学领域的接口工作，他目前在Flavell博士实验室的环境与Rakic博士的共同赞助使他处于完成拟议项目的指导阶段的理想环境中。Town博士的长期目标包括将自己确立为一名独立的科学家，并致力于了解阿尔茨海默病的神经免疫方面，希望为这种毁灭性疾病找到新的治疗靶点。Town博士的职业发展计划包括接受神经免疫学方面的培训和指导。在拟议的一年指导研究期之后，Town博士计划在拟议的奖项的帮助下向独立过渡。在指导期间，Town博士建议在一种转基因小鼠模型中评估阿尔茨海默病样病理学，该模型与一种阻断先天免疫细胞中TGF-β信号传导的转基因小鼠杂交。在指导阶段的拟议工作在很大程度上建立在初步数据的基础上，这些数据表明一只这样的杂交小鼠减轻了阿尔茨海默病样病理。对于独立阶段，Town博士将1）研究交叉小鼠中阿尔茨海默病病理学降低的潜在细胞机制，2）采用药物治疗方法，用TGF-β受体阻断抗体治疗阿尔茨海默病转基因小鼠，和3）进行另一项小鼠杂交实验，以确定阻断先天免疫细胞上的TGF-β信号传导是否可以缓解阿尔茨海默病-如在其初始建立期间或在活动性病变形成之后的病理学。相关性：阿尔茨海默病是美国最常见的痴呆症，据估计，超过300万65岁以上的美国人患有这种疾病。该项目旨在通过阻断一种蛋白质来发现治疗阿尔茨海默病的新途径，该蛋白质已被证明参与疾病的病理变化，特别是大脑的炎症反应。