Harnessing Proteins as Drugs: the Protectome of Cancer- and Aging-Prevention Proteins

利用蛋白质作为药物：抗癌和抗衰老蛋白质的保护组

• 批准号: 10012551
• 负责人: Susan M Rosenberg
• 金额: $ 448万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10012551
• 关键词: AD transgenic mice; Age; Aging; Alzheimer disease detection; Alzheimer disease screening; Alzheimer' s Disease; Amino Acids; Animal Model; Antisense Oligonucleotides; Award; Bacterial Model; Benign; Biological Assay; Biological Markers; Biology; Blood; Blood Pressure; Cancer Model; Cells; Charge; Clinical Trials; Computer software; DNA; DNA Damage; DNA Sequence Alteration; Data; Desiccation; Development; Diagnostic; Disease; Disease Progression; Disease Resistance; Disease model; Drug Screening; Early Diagnosis; Environment; Escherichia coli; Escherichia coli Proteins; Freedom; Genes; Genetic; Genetic Translation; Genome; Genomic Instability; Goals; Health Promotion; Heat shock proteins; Heat-Shock Proteins 90; Human; Individual; Insecta; Leukocytes; Libraries; Lipids; Malignant Neoplasms; Measures; Medical; Medicine; Methods; Modeling; Molecular; Molecular Chaperones; Mus; Mutagenesis; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Normal Cell; Organism; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Plants; Prevention; Production; Property; Proteins; Proteome; Quality Control; Resistance; Specificity; Stress; System; Technology; Testing; Up-Regulation; Work; age related; base; cancer prevention; cancer risk; design; disorder prevention; improved; inhibitor/antagonist; innovation; macromolecule; misfolded protein; new technology; overexpression; prevent; protein function; proteostasis; proteotoxicity; public health relevance; sex; success

Harnessing Proteins as Drugs—the Protectome of Cancer- and Aging-Prevention Proteins Alzheimer’s disease (AD) is a disease of toxic misfolded proteins, which both induce and are induced by poor proteostasis. Improving proteostasis appears to prevent AD in that the only cancers negatively correlated with Alzheimer’s are those that require and overproduce HSP90 protein chaperone. Because proteins maintain DNA, poor proteostasis also provokes DNA damage and mutations that in turn corrupt proteostasis. So increased DNA damage can be both a biomarker and driver of poor proteostasis and Alzheimer’s pathogenesis. This project has three central hypotheses centered on prevention of age-related diseases including Alzheimer’s: first, that cells can be made “better-than-normal” by upregulation of native proteins that shield cellular components from damaging agents, so that they tolerate or prevent genome instability and proteotoxicity. Upregulating these proteins could produce the most benign possible “drugs”—our own proteins—for prevention and treatment of diseases driven by genome instability and proteostasis decay, whether or not the genetic or environmental disease causes are known. However, these “molecular-shield” proteins have remained unknown because no technology was sensitive enough to find them by revealing cells with less DNA damage than in “normal” cells. Moreover, no technology has harnessed native proteins as “drugs,” by upregulation. Second, I hypothesize that natural proteins can be made into “proteoceutical” drugs by upregulating them pharmacologically—that exogenous agents could increase production of specific proteins to protect cells. Finally, I propose a sensitive blood-pressure-like general diagnostic for pre-disease and early detection of AD, cancer, and other age-associated diseases, using DNA-damage markers. This would identify individuals who need the proposed molecular-shield proteoceutical therapies. The molecular-shield proteins are likely to include, among others, (1) ubiquitous disordered stress-resistance proteins that form functional shields on interaction with diverse macromolecules, allowing them to function in otherwise toxic environments; (2) detoxifying proteins that rid cells of protein-, lipid- and DNA-damaging agents; (3) repressors of pathways that produce toxic byproducts; and (4) protein quality-control proteins. The goals of this project are to—(1) identify native molecular-shield proteins in the simple model organism E. coli and in human; and pioneer new technological paradigms for (2) a blood-based general diagnostic, using DNA-damage markers, for early and pre-disease detection of Alzheimer’s, neurodegeneration, cancer and other age-related diseases; and (3) creation of “proteoceutical drugs” from native human molecular-shield proteins, for use against AD and many medical problems. The results may form the basis of understanding a fundamentally new class of natural disease/AD-resistance proteins, detect individuals who may benefit from boosting them, and harness these and other proteins as health-promoting drugs.

利用蛋白质作为药物-癌症和衰老预防蛋白质的保护组 阿尔茨海默病（AD）是一种毒性错误折叠蛋白质的疾病，其既诱导蛋白质稳态不良，又由蛋白质稳态不良诱导。改善蛋白质稳态似乎可以预防AD，因为与阿尔茨海默病负相关的唯一癌症是那些需要和过度产生HSP 90蛋白伴侣的癌症。由于蛋白质维持DNA，蛋白质稳定性差也会引起DNA损伤和突变，进而破坏蛋白质稳定性。因此，DNA损伤的增加既可以是蛋白质稳定性差和阿尔茨海默病发病机制的生物标志物，也可以是驱动因素。该项目有三个中心假设，以预防包括阿尔茨海默氏症在内的与年龄相关的疾病为中心：首先，可以通过上调天然蛋白质使细胞“比正常情况更好”，这些蛋白质保护细胞成分免受破坏剂的影响，从而使它们耐受或预防基因组不稳定性和蛋白质毒性。上调这些蛋白质可以产生最良性的可能的“药物”-我们自己的蛋白质-用于预防和治疗由基因组不稳定性和蛋白质稳态衰变驱动的疾病，无论遗传或环境疾病的原因是已知的。然而，这些“分子盾”蛋白仍然是未知的，因为没有技术足够敏感，可以通过揭示比“正常”细胞DNA损伤更少的细胞来发现它们。此外，还没有技术通过上调天然蛋白质来利用天然蛋白质作为“药物”。其次，我假设天然蛋白质可以通过药理学上的上调而被制成“蛋白质药物”外源性药物可以增加特定蛋白质的产量来保护细胞。最后，我提出了一个敏感的血压一样的一般诊断疾病前和早期检测AD，癌症和其他年龄相关的疾病，使用DNA损伤标记。这将确定需要拟议的分子屏蔽蛋白质治疗的个体。 分子盾蛋白可能包括：（1）普遍存在的无序抗应激蛋白，它们与不同的大分子相互作用形成功能盾，使它们能够在其他有毒环境中发挥作用;（2）解毒蛋白，它们清除细胞中的蛋白质、脂质和DNA损伤剂;（3）产生有毒副产物的途径的阻遏物;和（4）蛋白质质量控制蛋白。 本项目的目标是：（1）在简单模式生物E.大肠杆菌和人;并开创了新的技术范例，用于（2）基于血液的一般诊断，使用DNA损伤标记物，用于阿尔茨海默氏症，神经变性，癌症和其他与年龄有关的疾病的早期和疾病前检测;（3）从天然人类分子盾蛋白质中创建“蛋白药物”，用于对抗AD和许多医学问题。这些结果可能成为理解一类全新的天然疾病/抗AD蛋白质的基础，检测可能受益于增强它们的个体，并利用这些蛋白质和其他蛋白质作为促进健康的药物。