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

• 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
• 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' 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

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）：目前已知大量不同的疾病，包括白内障、某些类型的青光眼、阿尔茨海默病、糖尿病和癌症，都具有聚集、错误折叠或修饰的蛋白质沉积物的共同特征。这组疾病的病理标志是蛋白质聚集和沉积在特定的细胞、组织或器官中。病理上的相似性表明，控制蛋白质相互作用的共同原则是蛋白质错误折叠退行性疾病的基础。因此，当每种疾病的蛋白质折叠/聚集问题相同时，为一种构象疾病开发的治疗模式也可能适用于另一种构象疾病。晶状体结晶蛋白聚集性白内障是一种典型的蛋白质错误折叠和聚集性疾病。随着时间的推移，晶状体中晶体蛋白聚集的累积效应导致与年龄相关的白内障形成。在某些形式的青光眼中，肌蛋白错误折叠并聚集在小梁网中，干扰房水的流出并引起眼压升高。该项目的目标是开发对蛋白质错误折叠和聚集发挥抑制作用的治疗性分子。我们的体外研究表明，在聚集蛋白中加入a-晶体蛋白可以阻止变性/展开蛋白的聚集和光散射的进一步增加。我们还发现a-crystallin亚基中的特定序列具有抑制变性蛋白聚集的能力。然而，a-晶蛋白衍生肽（迷你伴侣肽）的全部潜力尚未实现。我们建议开发1-晶体蛋白衍生的肽，并测试它们作为抑制晶体蛋白和心肌蛋白聚集的活性小伴侣的功能。具体目标如下：a)基于aa -晶体蛋白衍生的迷你伴侣蛋白序列，设计和合成蛋白-蛋白相互作用的肽调节剂。b)使用基于细胞培养的测定方法表征新鉴定的迷你伴侣的体内活性。特异性目的2：探讨微α -晶体蛋白伴侣抑制青光眼致突变心肌蛋白聚集的潜力。基于肽的蛋白质聚集性疾病治疗方法的成功开发将提供新的治疗方法。这些创新的研究将给我们提供新的见解，让我们了解蛋白质错误折叠疾病的潜在干预措施，不仅是眼睛疾病，还有身体其他部位的疾病。这一努力将扩大广泛的蛋白质错误折叠疾病的治疗策略。