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

项目摘要：这项提案的首要目标是调查 阻断阿尔茨海默病的转化生长因子-β信号转导。特伦斯镇， 博士目前是NRSA/NIA的博士后研究员，近期目标是再完成一年的工作 有指导的研究。唐恩博士一直致力于免疫学和神经科学的结合 菲尔兹和他目前在弗拉维尔博士实验室的环境，与拉基奇博士的立场共同赞助 他将在理想的环境中完成拟议项目的指导阶段。Dr。 唐恩的长期目标包括将自己确立为终身教职学者中的一名独立科学家 位置，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。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。在建议的一年辅导期之后 根据研究，唐恩博士计划在拟议的奖项的帮助下向独立过渡。 在指导期间，唐恩博士建议在转基因小鼠中评估类似阿尔茨海默病的病理 这种疾病的模型与一只转基因小鼠杂交，该转基因小鼠已经阻断了先天的转化生长因子-β信号 免疫细胞。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可以缓解阿尔茨海默病样的病理。对于独立阶段，Dr。 唐恩将研究降低阿尔茨海默病的潜在细胞机制 2)采用转化生长因子-β治疗阿尔茨海默病转基因小鼠的药物治疗方法 受体封闭抗体，以及3)进行另一次小鼠交叉实验，以确定是否封闭 先天免疫细胞上的转化生长因子-β信号转导减轻阿尔茨海默病初期的病理改变 或在活动性损伤形成之后。相关性：阿尔茨海默病是最常见的痴呆症 在美国，估计有超过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 这已被证明与疾病的病理变化有关，特别是大脑的 炎症反应。

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.