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

描述（由申请人提供）：该提案的首要目标是研究阻断转化生长因子-β (TGF-β) 信号传导对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，近期目标是完成额外一年的指导研究。 Town 博士一直致力于免疫学和神经科学领域的交叉领域工作，他目前在 Flavell 博士实验室的环境以及 Rakic 博士的共同赞助使他处于理想的环境中，可以在其中完成拟议项目的指导阶段。 Town 博士的长期目标包括使自己成为一名终身学术职位的独立科学家，并为了解阿尔茨海默病的神经免疫方面做出贡献，希望为这种毁灭性的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，汤博士计划在拟议奖项的帮助下过渡到独立。在指导期间，Town 博士建议在转基因小鼠模型中评估阿尔茨海默样病理学，该模型与阻断先天免疫细胞中 TGF-β 信号传导的转基因小鼠杂交。指导阶段拟议的工作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可以缓解阿尔茨海默样病理。在独立阶段，Town 博士将 1) 研究交叉小鼠中减少阿尔茨海默病病理的潜在细胞机制，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氏症转基因小鼠，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 信号传导是否可以减轻阿尔茨海默样病理在其最初建立期间或活动性病变形成后的情况。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已被证明参与阿尔茨海默氏病病理变化（特别是大脑炎症反应）的蛋白质，找到治疗阿尔茨海默氏病的新途径。

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.