Advancing Antibody Technology for tau Immunotherapies and for Investigating tau Pathogenesis

推进 tau 免疫疗法和研究 tau 发病机制的抗体技术

• 批准号: 9109233
• 负责人: Gilbert Gallardo
• 金额: $ 21.85万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9109233
• 关键词: Affinity; Antibodies; Behavior; Binding; Biochemical; Blood - brain barrier anatomy; Brain; Brain region; Cells; Chronic; Dependovirus; Disease; Engineering; Epitopes; Exhibits; Extracellular Domain; Extracellular Space; Fab Immunoglobulins; Faculty; Frontotemporal Lobar Degenerations; Gene Transfer; Goals; Health; Human; IGF Type 2 Receptor; Immunoglobulin Constant Region; Immunoglobulin Fragments; Immunoglobulin G; Immunotherapeutic agent; Immunotherapy; Inflammatory Response; Infusion procedures; Intercellular Fluid; Investigation; Knowledge; Low Density Lipoprotein Receptor; Lysosomes; MAPT gene; Measures; Mediating; Mentored Research Scientist Development Award; Mentors; Microglia; Molecular; Molecular Conformation; Monoclonal Antibodies; National Institute of Neurological Disorders and Stroke; Neurodegenerative Disorders; Neuroglia; Neurologist; Neurons; Neurosciences; Passive Immunization; Pathogenesis; Pathology; Positioning Attribute; Production; Progressive Supranuclear Palsy; Research; Research Personnel; Research Support; Role; Synapses; Tauopathies; Teacher Professional Development; Technology; Testing; Therapeutic; Time; Training; Translating; Translational Research; Transmembrane Domain; United States; Variant; adeno-associated viral vector; base; cell type; corticobasal degeneration; design; effective therapy; extracellular; gene therapy; improved; in vivo; member; mouse model; novel; prevent; prion-like; promoter; protective effect; receptor; response; tau Proteins; tau aggregation; theories

 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

 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受保护的时间，以获得独立研究支持，同时从指导职位过渡到学术神经科学领域的独立研究者。拟议的研究将为转化科学的应用提供理论和方法的新知识。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。拟议的研究将在 Holtzman 博士的指导下进行，其中候选人将研究 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 蛋白是 20 多种不同神经退行性疾病的核心组成部分，但目前尚无针对 tau 蛋白病的有效治疗方法。 Holtzman 实验室和其他实验室的最新研究表明，使用某些针对 tau 蛋白的单克隆抗体 (mAB) 进行被动免疫对 tau 蛋白病小鼠模型具有神经保护作用。 tau 免疫疗法有益效果的证据值得进一步研究，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蛋白作为免疫疗法靶标的出现以及最近证明tau蛋白病理学“扩散”现象的研究提出了一个问题：tau蛋白病理学的进展是否涉及tau蛋白病理学扩散中的细胞外单体和可能的寡聚tau蛋白。该项目的目标是确定免疫疗法与基因疗法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 神经保护活性中的作用来提高 tau 免疫疗法的疗效。此外，我们将确定细胞外空间中的 tau 蛋白是否促进 tau 蛋白病理学的传播，从而确定 tau 蛋白“类朊病毒”行为的机制。为了检验抗体介导的 tau 病理学减少不需要抗 tau 抗体 Fc 结构域以及 tau 细胞外形式介导细胞间 tau 扩散的假设，我们将研究以下目标： 1：为了长期治疗 tau 病，我们将开发一种体内抗 tau mAB 基因转移递送的策略。图 2：为了了解 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) 结构域效应器功能在体内 tau 免疫疗法中的作用。 3：为了研究 tau“类朊病毒”行为，我们将确定细胞外 tau 在 tau 病理学传播中的贡献