Advancing Antibody Technology for tau Immunotherapies and for Investigating tau Pathogenesis

 该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，以获得独立的研究支持，同时从导师职位过渡到学术神经科学的独立研究者。这些研究将为翻译科学的应用提供理论和方法上的新知识。此外，这些研究将为研究tau蛋白病中tau蛋白“朊病毒样”行为提供实验方面的培训。Holtzman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传播病理学传播的机制。尽管病理性tau是超过20种不同神经退行性疾病的中心组分，但目前没有有效的治疗tau蛋白病的方法。最近来自Holtzman实验室和其他人的研究表明，使用某些针对tau的单克隆抗体（mAB）的被动免疫在tau蛋白病的小鼠模型中具有神经保护作用。tau免疫疗法的有益作用的这一证据保证了进一步的研究，以提高tau免疫疗法的疗效，并确定长期治疗的递送模式。此外，tau作为免疫疗法的靶标的出现以及最近的研究证明了“扩散”tau病理学的现象，提出了tau病理学的进展是否涉及tau病理学扩散中的细胞外单体和可能的寡聚体tau的问题。该项目的目标是确定免疫治疗与基因治疗的组合是否是长期治疗的可行方法，并通过确定免疫球蛋白G（IgG）片段结晶（Fc）结构域在体内抗tau mAb的神经保护活性中的作用来提高tau免疫治疗的疗效。此外，我们将确定细胞外间隙中的tau是否促进tau病理学的传播，确定tau“朊病毒样”行为的机制。为了检验抗体介导的tau病变减少不需要抗tau抗体Fc结构域和细胞外形式的tau介导细胞间tau扩散的假设，我们将研究以下目的：1：对于tau病变的长期治疗，我们将开发用于体内基因转移递送抗tau mAB的策略。第二章：为了理解tau免疫疗法的功效，我们将确定免疫球蛋白G（IgG）片段可结晶（Fc）结构域效应子功能在体内tau免疫疗法中的作用。3：为了研究tau蛋白“朊病毒样”行为，我们将确定细胞外tau蛋白在tau蛋白病理学扩散中的作用。

 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