Closing the gap between structural biology and translational science for amyloid

缩小淀粉样蛋白结构生物学和转化科学之间的差距

• 批准号: 10630761
• 负责人: Lorena Saelices Gomez
• 金额: $ 6.78万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10630761
• 关键词: Amyloid; Amyloid Fibrils; Amyloid beta-Protein; Amyloidosis; Binding Proteins; Biology; Cells; Clinic; Coculture Techniques; Cryoelectron Microscopy; Deposition; Detection; Development; Diagnosis; Diagnostic; Disease; Disease model; Ensure; Etiology; Laboratories; Maps; Microtubules; Mus; Names; Pathologic; Patients; Peptides; Polymorph; Prealbumin; Prognosis; Proteins; Resolution; Role; Sampling; Structure; System; Tauopathies; Therapeutic; Translational Research; alpha synuclein; amyloid pathology; design; high risk; multidisciplinary; programs; protein TDP-43; structural biology; symptomatology; tau Proteins; tool

PROJECT SUMMARY/ABSTRACT The recent wave of cryo-electron microscopy (cryo-EM) studies on amyloid fibrils has highlighted the complexity of protein deposition amongst patients of amyloid diseases. A convincing example is found in tau, a microtubule binding protein whose pathological aggregation causes tauopathies. Each of these tauopathies seems to be associated with a particular structural assembly, suggesting causality. Similar to tauopathies, other amyloid diseases manifest differential prognosis, onset, and symptomatology. This is the case of TDP-43, α-synuclein, β-amyloid, or transthyretin (TTR), to name a few. We hypothesize that these phenotypical differences are driven by the formation of various structural assemblies, similar to what is found in tau. As a consequence, the detection of these disease-specific assemblies in a timely manner could ensure proper diagnosis and treatment. We aim to map the structural spectrum of amyloid fibrils in an amyloid disease model using cryo-EM and a co- culture system to be developed in our laboratory. Using the obtained structural information, our laboratory will design structure-specific peptides for the detection and inhibition of amyloid fibrils in cells, mice, and patient- derived samples. If successful, our study will serve as a launching platform for the development of personalized structure-based diagnostics and therapeutics for amyloid diseases.

项目摘要/摘要 最近对淀粉样纤维的冷冻电子显微镜（Cryo-EM）研究突出了复杂性 淀粉样蛋白疾病患者的蛋白质沉积。在微管Tau中发现了一个令人信服的例子 结合蛋白的病理聚集会引起auopathies。这些tauopathies似乎是 与特定的结构组装相关，提示因果关系。类似于tauopathies，其他淀粉样蛋白 疾病表现出差异预后，发作和症状学。 TDP-43，α-突触核蛋白就是这种情况 β-淀粉样蛋白（TTR）等。我们假设这些表型差异是驱动的 通过形成各种结构组件，类似于tau中的结构组件。结果，检测 在这些特定疾病的组件中，及时可以确保适当的诊断和治疗。 我们的目的是使用冷冻EM和共同的淀粉样蛋白疾病模型中的淀粉样蛋白原纤维的结构光谱绘制 在我们的实验室中开发的文化系统。使用获得的结构信息，我们的实验室将 设计结构特异性的辣椒，用于检测和抑制细胞，小鼠和患者的淀粉样蛋白原纤维 派生样品。如果成功，我们的研究将成为开发个性化的启动平台 基于结构的诊断和淀粉样蛋白疾病的疗法。