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: 7564944
• 负责人: TERRENCE C TOWN
• 金额: $ 24.9万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 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 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7564944
• 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

PROJECT SUMMARY: 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.

项目总结：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。特伦斯镇， 博士目前是NRSA/NIA博士后研究员，近期目标是再完成一年 of mentored指导research研究. Town博士一直致力于免疫学和神经科学的研究 领域，以及他目前在Flavell博士实验室的环境与Rakic博士的共同赞助。 他在理想的环境中完成了拟议项目的指导阶段。博士 汤的长期目标包括在一个终身制的学术机构中成为一名独立的科学家。 立场，并有助于了解阿尔茨海默病的神经免疫方面，希望 为这种毁灭性的疾病寻找新的治疗靶点。Dr. Town的职业发展计划包括 接受神经免疫学方面的培训和指导。在拟议的一年辅导期结束后， 在研究的基础上，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博士建议在转基因小鼠中评估阿尔茨海默病样病理学 这种疾病的模型与一种在先天性免疫缺陷中阻断TGF-β信号传导的转基因小鼠杂交， 免疫细胞。指导阶段的拟议工作主要基于初步数据，这些数据表明 一只这样的杂交小鼠具有阿尔茨海默病样病理的减轻。对于独立阶段，博士。 Town将1）研究交叉研究中阿尔茨海默病病理学降低的潜在细胞机制， 小鼠，2）通过用TGF-β治疗阿尔茨海默氏症转基因小鼠， 受体阻断抗体，和3）进行另一次小鼠杂交实验，以确定是否阻断 先天性免疫细胞上的TGF-β信号传导在其最初建立期间减轻阿尔茨海默病样病理 或在形成活动性损伤之后。相关性：阿尔茨海默病是最常见的痴呆症 在美国，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揭示治疗阿尔茨海默病的新途径 已经被证明与疾病的病理变化有关，特别是大脑的 炎症反应。