Advancing Antibody Technology for tau Immunotherapies and for Investigating tau Pathogenesis

 描述(由申请人提供)：NINDS教师发展奖(K01)的目标是为初级教师提供支持和保护时间，使其在从学术神经科学的指导职位过渡到独立研究人员的过程中获得独立研究支持。拟议的研究将为翻译科学的应用提供新的理论和方法方面的知识。此外，这些研究还将为研究tau病中的tau类Prion行为提供实验方面的培训。这项拟议的研究将在霍尔茨曼博士的指导下进行，候选人将研究tau免疫疗法、基因疗法以及tau传播病理的机制。虽然病理性tau是20多种不同神经退行性疾病的中心组成部分，但目前还没有有效的治疗tau病的方法。霍尔兹曼实验室和其他实验室最近的研究表明，使用某些针对tau的单抗(MAb)进行被动免疫对tau病小鼠模型具有神经保护作用。这一证据证明了tau免疫疗法的有益效果，值得进一步研究，以提高tau免疫疗法的疗效，并确定长期治疗的给药方式。此外，tau作为免疫治疗靶点的出现以及最近的研究证实了tau病理的“扩散”现象，提出了tau病理的进展是否涉及细胞外单体和可能的寡聚tau参与tau病理的扩散的问题。本项目的目的是通过确定免疫球蛋白G(Ig G)片段结晶(Fc)结构域在体内抗tau单抗神经保护活性中的作用，确定免疫治疗与基因治疗相结合是否是一种可行的长期治疗方法，并提高tau免疫治疗的疗效。此外，我们还将确定细胞外间隙中的tau是否促进tau病理的传播，以确定tau“普赖恩样蛋白”行为的机制。为了验证抗体介导的tau病变减少不需要抗tau抗体Fc结构域，以及细胞外形式的tau介导细胞间tau扩散的假设，我们将检验以下目标：1：为了长期治疗tau病，我们将开发一种体内抗tau单抗的基因转移递送策略。2：为了了解tau免疫治疗的疗效，我们将在体内研究免疫球蛋白G(Ig G)片段结晶(Fc)结构域效应功能在tau免疫治疗中的作用。3：为了研究tau的“普恩样蛋白”行为，我们将确定细胞外tau在tau病理传播中的作用。

 DESCRIPTION (provided by applicant): The goal of this NINDS Faculty Development Award (K01) is to provide support and protected time for a junior faculty member to obtain independent research support while transitioning from a mentored position to an independent investigator in academic neuroscience. The proposed studies will provide new knowledge on the theory and methodological approaches for the application of translational science. In addition, these studies will provide training in the experimental aspects for studying tau "prion-like" behavior in tauopathies. The research proposed will be conducted under the mentoring of Dr. Holtzman, in which the candidate will investigate tau immunotherapies, gene therapy, and mechanisms by which tau propagates the spread of pathology. Although pathological tau is a central component of over 20 distinct neurodegenerative diseases there is currently no effective treatment for tauopathies. Recent studies from the Holtzman lab and others have demonstrated that passive immunizations using certain monoclonal antibodies (mABs) against tau are neuro-protective in mouse models of tauopathies. This evidence for the beneficial effects of tau immunotherapy warrants further investigation for improving the efficacy of tau immunotherapies and for determining a mode of delivery for long-term treatment. Furthermore, the emergence of tau as a target for immunotherapies together with recent studies demonstrating the phenomenon of "spreading" tau pathology raises the question whether the progression of tau pathology involves extracellular monomeric and possibly oligomer tau in the spreading of tau pathology. The goals of this project are to determine whether a combination of immunotherapy with gene therapy is a feasible approach for long-term treatment and to improve the efficacy of tau immunotherapy by determining the role of the immunoglobulin G (IgG) fragment crystallize (Fc) domain in the neuro-protective activity of anti-tau mABs in vivo. Additionally, we will determine whether tau in the extracellular space promotes the spread of tau pathology identifying a mechanism for tau "prion-like" behavior. To test the hypothesis that antibody-mediated decrease in tau pathology does not require anti-tau antibody Fc domain and that extracellular forms of tau mediate cell to cell tau spreading, we will examine the following Aims: 1: For long-term treatment of tauopathies we will develop a strategy for gene transfer delivery of anti-tau mABs in vivo. 2: To understand the efficacy of tau immunotherapy we will determine the roles for the immunoglobulin G (IgG) fragment crystalizable (Fc) domain effector function in tau immunotherapy in vivo. 3: To investigate tau "prion-like" behavior we will determine the contribution of extracellular tau in th spreading of tau pathology