Crystallin-Derived Mini-Chaperones as Protein Aggregation Inhibitors

晶状体蛋白衍生的微型伴侣作为蛋白质聚集抑制剂

基本信息

批准号：
7976444
负责人：
KRISHNA K SHARMA
金额：
$ 22.73万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7976444
关键词：
Adolescent Adult Affect Alzheimer&apos s Disease Amyloid deposition Aqueous Humor Biological Assay Blood - brain barrier anatomy Body part Cataract Cell Culture Techniques Cells Characteristics Chemicals Crystallins Degenerative Disorder Deposition Development Diabetes Mellitus Disease Electrostatics Eye Eye diseases Gene Expression Genes Glaucoma Goals Half-Life In Vitro Intervention Malignant Neoplasms Methods Modality Molecular Chaperones Names Organ Peptides Physiologic Intraocular Pressure Play Prion Diseases Process Proteins Research Retinal Role Sickle Cell Anemia Testing Therapeutic Therapeutic Effect Time Tissues Trabecular meshwork structure age related base design in vivo inhibitor/antagonist innovation insight lens lens protein light scattering mutant myocilin novel novel therapeutic intervention novel therapeutics prevent protein aggregate protein aggregation protein folding protein misfolding protein phosphatase inhibitor-2 protein protein interaction public health relevance synthetic peptide therapeutic protein therapy development

Adolescent Adult Affect Alzheimer&apos s Disease Amyloid deposition Aqueous Humor Biological Assay Blood - brain barrier anatomy Body part Cataract Cell Culture Techniques Cells Characteristics Chemicals Crystallins Degenerative Disorder Deposition Development Diabetes Mellitus Disease Electrostatics Eye Eye diseases Gene Expression Genes Glaucoma Goals Half-Life In Vitro Intervention Malignant Neoplasms Methods Modality Molecular Chaperones Names Organ Peptides Physiologic Intraocular Pressure Play Prion Diseases Process Proteins Research Retinal Role Sickle Cell Anemia Testing Therapeutic Therapeutic Effect Time Tissues Trabecular meshwork structure age related base design in vivo inhibitor/antagonist innovation insight lens lens protein light scattering mutant myocilin novel novel therapeutic intervention novel therapeutics prevent protein aggregate protein aggregation protein folding protein misfolding protein phosphatase inhibitor-2 protein protein interaction public health relevance synthetic peptide therapeutic protein therapy development

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项目摘要

DESCRIPTION (provided by applicant): A large number of diverse diseases, including cataract, some types of glaucoma, Alzheimer disease, diabetes and cancer to name only a few, are now known to share the common feature of aggregated, misfolded or modified protein deposits. The pathological hallmark in this group of diseases is protein aggregation and deposition in specific cells, tissues or organs. The pathological similarities indicate that common principles that govern protein interactions underlie protein misfolding degenerative diseases. Therefore, a therapeutic modality developed for one conformational disease might also be applicable to another conformational disease when the protein folding/aggregation problem is the same in each disease. Lens crystallin aggregation and cataractogenesis is a classic example of a protein misfolding and aggregation disease. Over time, the cumulative effects of crystallin aggregation in the lens results in age-related cataract formation. In certain forms of glaucoma, the protein myocilin misfolds and aggregates in the trabecular meshwork, interfering with the outflow of aqueous humor and causing elevated intraocular pressure. The goal of this project is to develop therapeutic molecules that exert inhibitory actions on protein misfolding and aggregation. Our in vitro studies have shown that the addition of a-crystallin to aggregating proteins stops a further increase in aggregation and light scattering of denaturing/unfolding proteins. We have also found that specific sequences in a-crystallin subunits have the capacity to suppress aggregation of denaturing proteins. However, the full potential of a-crystallin-derived peptides (mini-chaperones) is yet to be realized. We propose to develop 1-crystallin-derived peptides and test their function as active mini-chaperones capable of suppressing crystallin and myocilin protein aggregation. The Specific Aims are the following: Specific Aim 1. a) Design and synthesize peptide modulator(s) of protein-protein interactions based on the aA-crystallin-derived mini-chaperone sequence. b) Characterize the in vivo activity of the newly identified mini-chaperone(s) using cell culture-based assay methods. Specific Aim 2: Investigate the potential of mini-aA-crystallin chaperone for suppressing aggregation of glaucoma-causing mutant myocilin. Successful development of peptide-based therapeutics for protein aggregation diseases will offer new therapeutic approaches. These innovative studies will give us new insights into potential interventions for protein misfolding diseases, not only of the eye but also of other parts of the body. This effort would expand the therapeutic strategies for wide range of protein misfolding diseases. PUBLIC HEALTH RELEVANCE: Cataract and glaucoma, along with a host of other diseases, result from abnormal interaction of proteins in the cells. The goals of this research are to develop and test lens protein 1-crystallin-derived peptides as active mini-chaperones capable of suppressing protein aggregation.

描述（由申请人提供）：现在众所周知，大量各种疾病，包括白内障，某些类型的青光眼，阿尔茨海默氏病，糖尿病和癌症，只有少数疾病，可以共享聚集，错误折叠或修饰的蛋白质沉积物的共同特征。这组疾病中的病理标志是特定细胞，组织或器官中的蛋白质聚集和沉积。病理相似性表明，控制蛋白质相互作用的常见原理是蛋白质错误折叠疾病的基础。因此，当蛋白质折叠/聚集问题在每种疾病中相同时，针对一种构象疾病开发的治疗方式也可能适用于另一种构象疾病。晶状体结晶蛋白聚集和白内生生成是蛋白质错误折叠和聚集疾病的经典例子。随着时间的流逝，晶状体聚集在晶状体中的累积作用会导致与年龄相关的白内障形成。在某些形式的青光眼中，小梁网中蛋白肌动蛋白的折叠和聚集体不折叠和聚集体，干扰水幽默的流出并导致眼内压力升高。该项目的目的是开发对蛋白质错误折叠和聚集作用抑制作用的治疗分子。我们的体外研究表明，在聚集蛋白质中添加A-结晶蛋白会阻止变性/展开蛋白的聚集和光散射进一步增加。我们还发现，A-晶状体亚基中的特定序列具有抑制变性蛋白聚集的能力。但是，尚未实现A-结晶蛋白衍生的肽（迷你链蛋白）的全部潜力。我们建议开发1-结晶蛋白衍生的肽，并测试其功能，作为能够抑制结晶蛋白和肌动蛋白蛋白聚集的活性迷你链蛋白。具体目的是：特定目标1。a）基于AA-晶状体衍生的微型纤维酮序列的蛋白质 - 蛋白质相互作用的设计和合成肽调节剂。 b）使用基于细胞培养的测定方法来表征新鉴定的微型核心的体内活性。具体目标2：研究迷你蛋白结晶蛋白伴侣伴侣抑制引起青光眼突变体肌动蛋白的聚集的潜力。成功开发基于肽的蛋白质聚集疾病的疗法将提供新的治疗方法。这些创新的研究将为我们提供有关蛋白质错误折叠疾病的潜在干预措施的新见解，不仅是眼睛，而且对身体的其他部位。这项工作将扩大针对各种蛋白质错误折叠疾病的治疗策略。公共卫生相关性：白内障和青光眼以及许多其他疾病，是由于细胞中蛋白质异常相互作用引起的。这项研究的目标是开发和测试晶状体蛋白1-晶状蛋白衍生的肽作为活跃的微型链蛋白，能够抑制蛋白质聚集。