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

描述(申请人提供)：这项提案的首要目的是研究阻断转化生长因子-β(转化生长因子-β)信号对阿尔茨海默病的治疗潜力。特伦斯·敦博士目前是NRSA/NIA的博士后研究员，近期目标是完成一年的导师研究。唐恩博士一直致力于免疫学和神经科学领域的工作，他目前在弗拉维尔博士实验室与拉基奇博士共同赞助的环境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。唐恩博士的长期目标包括确立自己作为终身教职的独立科学家的地位，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。唐恩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之后，唐恩博士计划在拟议的奖项的帮助下过渡到独立。在指导期间，唐恩博士建议在转基因小鼠的阿尔茨海默病模型中评估类似阿尔茨海默氏症的病理改变，转基因小鼠已经阻断了先天免疫细胞中的转化生长因子-β信号。在指导阶段提出的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，这样一只杂交的小鼠可以缓解阿尔茨海默病样的病理。在独立阶段，唐恩博士将1)研究交叉小鼠阿尔茨海默病病理减少的潜在细胞机制，2)采用药物治疗方法，用转化生长因子-β受体阻断抗体治疗阿尔茨海默病转基因小鼠，以及3)进行另一次小鼠交叉实验，以确定在阿尔茨海默病初期或活动性皮损形成后，阻断先天免疫细胞上的转化生长因子-β信号是否能缓解阿尔茨海默病样病理。相关性：阿尔茨海默病是美国最常见的痴呆性疾病，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，这种蛋白质已被证明与阿尔茨海默病的病理变化有关，特别是大脑的炎症反应。

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.