Developing Diagnostic Nanobodies Against Aggregated TDP-43 Species

开发针对聚集的 TDP-43 物种的诊断纳米抗体

• 批准号: 8517544
• 负责人: MICHAEL R SIERKS
• 金额: $ 18.27万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8517544
• 关键词: Alzheimer' s Disease; Amyloid beta-Protein; Amyotrophic Lateral Sclerosis; Antibodies; Asses; Binding; Biological Markers; Biosensor; Brain; Cellular Stress; Dementia; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Disease Progression; Event; Goals; Human; Huntington Disease; Immunoglobulin Fragments; Lead; Lewy Body Dementia; Monitor; Morphology; Neurodegenerative Disorders; Neurons; Parkinson Disease; Patients; Process; Proteins; Reagent; Sampling; Serum; Specificity; Staging; Structure; Tauopathies; Testing; Therapeutic; Tissues; Traumatic Brain Injury; Variant; alpha synuclein; base; brain tissue; direct application; disease diagnosis; extracellular; human Huntingtin protein; nanobodies; new technology; protein TDP-43; protein aggregate; protein aggregation; protein misfolding; tau Proteins; therapeutic target; treatment strategy

DESCRIPTION (provided by applicant): Protein misfolding and aggregation is a common thread behind many neurodegenerative diseases including Alzheimer's disease (AD), Lewy Body Dementia (LBD), and Parkinson's disease (PD) among others. While each disease has been primarily associated with aggregation of a specific protein; beta-amyloid (abeta) with AD, tau with AD and other tauopathies, alpha-synuclein (¿-syn) with PD and LBD, more than one protein is likely to misfold and aggregate in brain tissue complicating diagnosis and treatment strategies. Aggregation of another neuronal protein, TDP-43, has been strongly correlated with amyotrophic lateral sclerosis (ALS) and Frontal Temporal Dementia (FTD) and has also been associated with traumatic brain injury and AD among other neurodegenerative disorders. Since cellular stress induced by misfolding and aggregation of one protein such as abeta may well lead to misfolding and aggregation of other proteins such as ¿-syn, tau and TDP-43, the presence of multiple misfolded proteins in different diseases should be expected. Therefore characterizing which aggregated protein species are correlated with different stages of each disease would greatly facilitate development of better diagnostic and treatment strategies. We have generated several well characterized reagents that specifically recognize different aggregated species of abeta and ¿-syn, and have demonstrated that the reagents recognize aggregated species occurring in tissue from diseased brains, but not healthy brains, and that the reagents can have disease specificity as well. Here we will develop and test similar reagents for detecting specific forms of TDP-43 that are present in FTD and ALS brain tissue.

描述（由申请人提供）：蛋白质错误折叠和聚集是许多神经退行性疾病背后的共同线索，包括阿尔茨海默病（AD）、路易体痴呆（LBD）和帕金森病（PD）等。虽然每种疾病主要与特定蛋白质的聚集有关; β-淀粉样蛋白（abeta）与AD，tau与AD和其他tau蛋白病，α-突触核蛋白（n-syn）与PD和LBD，一种以上的蛋白质可能在脑组织中错误折叠和聚集，使诊断和治疗策略复杂化。另一种神经元蛋白TDP-43的聚集与肌萎缩侧索硬化症（ALS）和额颞痴呆（FTD）密切相关，并且还与创伤性脑损伤和AD以及其他神经退行性疾病相关。由于由一种蛋白质如abeta的错误折叠和聚集诱导的细胞应激很可能导致其他蛋白质如<$-syn、tau和TDP-43的错误折叠和聚集，因此应预期在不同疾病中存在多种错误折叠蛋白质。因此，表征哪种聚集蛋白种类与每种疾病的不同阶段相关将极大地促进更好的诊断和治疗策略的开发。我们已经产生了几种充分表征的试剂，其特异性地识别Abeta和？-syn的不同聚集种类，并且已经证明所述试剂识别来自患病大脑而不是健康大脑的组织中出现的聚集种类，并且所述试剂也可以具有疾病特异性。在这里，我们将开发和测试类似的试剂，用于检测FTD和ALS脑组织中存在的TDP-43的特定形式。

项目成果

Novel atomic force microscopy based biopanning for isolation of morphology specific reagents against TDP-43 variants in amyotrophic lateral sclerosis.

基于新型原子力显微镜的生物淘选，用于分离针对肌萎缩侧索硬化症中 TDP-43 变体的形态特异性试剂。

• DOI: 10.3791/52584
• 发表时间: 2015
• 期刊: Journal of visualized experiments : JoVE
• 作者: Williams,StephanieM;Venkataraman,Lalitha;Tian,Huilai;Khan,Galam;Harris,BrentT;Sierks,MichaelR
• 通讯作者: Sierks,MichaelR

Isolation and characterization of antibody fragments selective for human FTD brain derived TDP-43 variants.

对人 FTD 脑源性 TDP-43 变体具有选择性的抗体片段的分离和表征。

• DOI: 10.1186/s12868-020-00586-0
• 发表时间: 2020
• 期刊: BMC neuroscience
• 影响因子: 2.4
• 作者: Venkataraman,Lalitha;He,Ping;Khan,Galam;Harris,BrentT;Sierks,MichaelR
• 通讯作者: Sierks,MichaelR

TDP-43 protein variants as biomarkers in amyotrophic lateral sclerosis.

TDP-43蛋白变异作为肌萎缩性侧硬化症中的生物标志物。

• DOI: 10.1186/s12868-017-0334-7
• 发表时间: 2017-01-25
• 期刊: BMC neuroscience
• 影响因子: 2.4
• 作者: Williams SM;Khan G;Harris BT;Ravits J;Sierks MR
• 通讯作者: Sierks MR