Understanding the antagonistic role of proteostasis in Alzheimer disease and cancer.

了解蛋白质稳态在阿尔茨海默病和癌症中的拮抗作用。

• 批准号: 10118671
• 负责人: Alexander Richard Mendenhall
• 金额: $ 37.57万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10118671
• 关键词: Affect; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Animal Model; Animals; Attenuated; Awareness; Biological Models; Brain; Caenorhabditis elegans; Cells; Dementia; Development; Disease; Dose; Elderly; Epidemiology; Frontotemporal Dementia; Funding; Future; Glioblastoma; Goals; Human; Immune; Impairment; Investigative Reports; Letters; Malignant Neoplasms; Malignant neoplasm of brain; Modeling; Molecular Chaperones; Mutation; Neoplasms; Neurodegenerative Disorders; Oncogenes; Outcome; Parkinson Disease; Pathology; Penetrance; Peptides; Peripheral; Phenotype; Population; Production; Property; Proteins; Proteome; Research; Research Design; Role; Running; Severities; Societies; Subcutaneous Tissue; System; Testing; Toxic effect; alpha synuclein; base; cancer risk; design; dosage; gain of function; gain of function mutation; genetic approach; hyperphosphorylated tau; immune function; insight; interest; misfolded protein; overexpression; parent grant; protein aggregation; protein misfolding; proteostasis; tau Proteins; tumor; tumor progression

Project Summary: There is an inverse relationship between cancer and neurodegenerative disease. Specifically, people with Alzheimer’s disease have a lower risk of cancer and vice versa. While there is evidence that immune function underlies the relationship between non-brain cancer and neurodegenerative disease, we hypothesize that there is a different cause for this inverse relationship in brain cancers. We believe proteostasis lies at the core of this relationship for brain cancer. We believe toxic peptides associated with neurodegenerative diseases cause the cells expressing or containing them to have a decreased ability to produce and maintain functional proteins. This would mean that these cells with these toxic peptides would have lower effective dosages of oncogenes. Alzheimer’s disease (AD) and other dementias are increasingly thought of as diseases of protein misfolding. Accordingly, much research has found that treatments that increase cells’ abilities to manage misfolded or aggregated proteins tend to decrease the severity of AD-related phenotypes in model systems. Overexpression of chaperones tends to suppress AD-related pathologies. Conversely, cancer is a disease wherein oncogene expressing cells that manage misfolded proteins better, tend to comprise more aggressive tumors. Therefore, managing misfolded proteins is good for the progression of cancer and bad for the progression of AD and other neurodegenerative diseases where aggregate management currently seems to be a critical component of the diseases. Thus, there is an antagonistic role for proteostasis in cancer and AD. AD and other neurodegenerative disorders cause a significant burden to the proteostatic systems. We believe that it is this burden that decreases the proteostatic capacities of cells in the brain, and is the cause of the inverse relationship between AD and various brain cancers, especially glioblastoma, where Ras is a critical component. We believe this because increased chaperone capacity, which begets increased general proteostasis causes more severe neoplasia formation in our animal model of Ras-based cancer. Additionally, higher expression of chaperones decreases the severity of phenotypes caused by toxic peptides (Aβ, Tau and α-synuclein) in the same animal model system. In the proposed research, we aim to understand how toxic peptides associated with neurodegenerative diseases affect Ras-driven neoplasia formation. Conversely, we will determine how phenotypes caused by these same toxic peptides are changed by nullification or overexpression of chaperones that we have found to modulate Ras-driven neoplasia formation in our currently funded research designed to understand what factors cause the incomplete penetrance of neoplasia formation. Thus, in the proposed research we will take a genetic approach to understand the inverse relationship between brain cancer and neurodegenerative disease.

项目总结： 癌症和神经退行性疾病之间存在着相反的关系。具体地说，患有 阿尔茨海默病患癌症的风险较低，反之亦然。虽然有证据表明免疫功能 非脑癌和神经退行性疾病之间的关系，我们假设 是脑癌中这种反向关系的另一个原因。我们认为蛋白质代谢是这一现象的核心 与脑癌的关系。我们认为与神经退行性疾病相关的有毒多肽会导致 表达或含有它们的细胞产生和维持功能的能力降低 蛋白质。这将意味着含有这些有毒多肽的细胞将具有较低的有效剂量 致癌基因。 阿尔茨海默病(AD)和其他痴呆症越来越被认为是蛋白质错误折叠的疾病。 因此，许多研究发现，提高细胞管理错误折叠或折叠的能力的治疗 在模型系统中，聚集的蛋白质往往会降低AD相关表型的严重性。 伴侣蛋白的过度表达往往会抑制AD相关的病理过程。相反，癌症是一种疾病。 其中，癌基因表达的细胞对错误折叠的蛋白质处理得更好，往往包含更具侵略性的 肿瘤。因此，处理错误折叠的蛋白质有利于癌症的进展，而不利于癌症的发展 AD和其他神经退行性疾病的进展，目前似乎是集合管理 成为疾病的关键组成部分。因此，蛋白平衡在癌症和阿尔茨海默病中具有拮抗作用。 AD和其他神经退行性疾病给蛋白质平衡系统带来了巨大的负担。我们相信 正是这种负担降低了大脑中细胞的蛋白稳定能力，也是导致 AD与多种脑癌，特别是胶质母细胞瘤之间的负相关，其中RAS是一个关键的 组件。我们相信这一点是因为监护人能力的增加，这导致了更多的一般 在我们以RAS为基础的癌症动物模型中，蛋白平衡导致更严重的肿瘤形成。另外， 伴侣蛋白的高表达降低了毒肽(Aβ、Tau和Tau)引起的表型严重性 α-突触核蛋白)在相同的动物模型系统中。 在这项拟议的研究中，我们的目标是了解有毒多肽与神经退行性变之间的关系 疾病影响RAS驱动的肿瘤形成。相反，我们将确定表型如何导致 同样的毒肽也会因我们所拥有的伴侣蛋白的无效或过度表达而改变 在我们目前资助的研究中发现调节RAS驱动的肿瘤形成，旨在了解 是什么因素导致肿瘤的不完全穿透形成。因此，在拟议的研究中，我们 将采用遗传学的方法来理解脑癌和癌症之间的反向关系 神经退行性疾病。