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

基本信息

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
项目类别：
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

项目摘要

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点，包括阿尔茨海默病（AD）、路易体痴呆（LBD）和帕金森病（PD）等，而每种疾病主要与这些疾病相关。特定蛋白质的聚集；β-淀粉样蛋白 (abeta) 与 AD、tau 蛋白与 AD 和其他 tau 病、α-突触核蛋白(¿-syn) 与 PD 和 LBD 相比，不止一种蛋白质可能会在脑组织中强烈错误折叠和聚集，从而使另一种神经元蛋白质 TDP-43 的聚集与肌萎缩侧索硬化症 (ALS) 相关。和额颞叶痴呆 (FTD)，并且还与创伤性脑损伤和 AD 等其他神经退行性疾病有关，因为细胞应激是由一种蛋白质的错误折叠和聚集引起的。因为 abeta 很可能导致其他蛋白质的错误折叠和聚集，例如 ¿ -syn、tau 和 TDP-43，不同疾病中存在多种错误折叠蛋白，因此，确定哪些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。几种特征明确的试剂，可特异性识别 abeta 和 ¿ 的不同聚集种类-syn，并证明这些试剂可以识别患病大脑组织中出现的聚集物质，但不能识别健康大脑，并且这些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来检测特定形式的 TDP-。 43 存在于 FTD 和 ALS 脑组织中。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
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。