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Intracellular tools to study specific misfolded protein variants in human disease

研究人类疾病中特定错误折叠蛋白质变异的细胞内工具

基本信息

批准号：
8307797
负责人：
MICHAEL R SIERKS
金额：
$ 15.34万
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：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8307797
关键词：
Address Alzheimer&apos s Disease Amino Acids Amyloid beta-Protein Amyotrophic Lateral Sclerosis Ankyrin Repeat Antigen Targeting Apoptosis Binding Binding Proteins Cell Culture Techniques Cell Differentiation process Cell Line Cell physiology Cell secretion Cells Clear Cell Cytosol Development Diabetes Mellitus Diagnosis Disease Disease Progression Engineering Environment Equus caballus Event Excision Functional disorder Gene Expression Genes Genomics Goals Health Human Huntington Disease Immunoglobulin Fragments In Situ Individual Lead Libraries Location Lysosomes Malignant Neoplasms Mammalian Cell Methods Molecular Chaperones Molecular Conformation Morphology Neurodegenerative Disorders Nuclear Parkinson Disease Pathway interactions Phage Display Prions Process Proteins Proteomics RNA RNA Interference Randomized Reagent Recombinant Antibody Recombinant Proteins Research Role Scientist Signal Pathway Signal Transduction Site Small Interfering RNA Stem cells Superoxide Dismutase Techniques Testing Therapeutic Toxic effect Variant Viral Proteins Virus Diseases alpha synuclein base brain tissue design fluorophore human Huntingtin protein human disease improved islet amyloid polypeptide multicatalytic endopeptidase complex nanobodies new technology novel prion-based protein complex protein degradation protein folding protein misfolding protein misfolding and misprocessing protein misprocessing stem cell differentiation tau Proteins therapeutic protein tool trafficking tumor

项目摘要

DESCRIPTION (provided by applicant): Intracellular misfolding or misprocessing of proteins is a critical problem in numerous human diseases including neurodegenerative disorders, diabetes and cancer. The ability to specifically target and manipulate individual protein variants in situ would be a powerful tool in treating these diseases. Inhibitory RNA techniques have revolutionized cell studies, providing the ability to selectively inhibit expression of single genes. Many diseases and cellular processes however result from aberrant protein folding or processing, or from formation of protein complexes, events which cannot be controlled by RNAi. A powerful complementary approach to RNAi techniques would be the ability to selectively target and manipulate a misfolded, misprocessed or complexed protein form intracellularly. In this proposal we will develop reagents that can bind specific protein variants using robust intracellular protein frameworks. Different tags can be added to target specific cell locations and pathways including proteasomes and lysosomes for protein degradation, endosomal targeting for cell internalization, and cell secretion for protein removal. A variety of very exciting applications can be addressed including: 1) targeting misfolded and misprocessed proteins involved in human health problems including neurodegenerative diseases, diabetes and cancer, 2) targeting cell signaling pathways to control apoptosis in diseased cells or differentiation in stem cells, 3) developing chaperone-like reagents that can promote correct protein folding in situ, and 4) targeting viral proteins involved in replication or assembly to provide a means to control viral infection especially in brain tissue. The overall goal of this project is to develop reagents that can be readily modified to intracellularly bind a selected target protein variant and manipulate that target in a predictable manner to achieve a desired result. This ability to manipulate specific intracellular targets can have profound impact on numerous health problems.

描述（由申请人提供）：蛋白质的细胞内错误折叠或错误加工是许多人类疾病（包括神经退行性疾病、糖尿病和癌症）中的关键问题。特异性靶向和原位操纵单个蛋白质变体的能力将是治疗这些疾病的有力工具。抑制性RNA技术彻底改变了细胞研究，提供了选择性抑制单个基因表达的能力。然而，许多疾病和细胞过程是由异常的蛋白质折叠或加工，或由蛋白质复合物的形成引起的，这些事件不能被RNAi控制。RNAi技术的一个强有力的补充方法是能够选择性地靶向和操纵细胞内错误折叠、错误加工或复合的蛋白质形式。在这项提案中，我们将开发可以使用强大的细胞内蛋白质框架结合特定蛋白质变体的试剂。可以添加不同的标签以靶向特定的细胞位置和途径，包括用于蛋白质降解的蛋白酶体和溶酶体、用于细胞内化的内体靶向和用于蛋白质去除的细胞分泌。可以解决各种非常令人兴奋的应用，包括：1）靶向与包括神经变性疾病、糖尿病和癌症在内的人类健康问题有关的错误折叠和错误加工的蛋白质，2）靶向细胞信号传导途径以控制患病细胞中的凋亡或干细胞中的分化，3）开发可以促进原位正确蛋白质折叠的分子伴侣样试剂，和4）靶向参与复制或装配的病毒蛋白质，以提供控制病毒感染的手段，特别是在脑组织中。该项目的总体目标是开发可以轻易修饰的试剂，以在细胞内结合选定的靶蛋白变体，并以可预测的方式操纵该靶点以实现所需的结果。这种操纵特定细胞内靶点的能力可以对许多健康问题产生深远的影响。