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

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)是一种由有毒蛋白质错误折叠引起的疾病，这种疾病既可以诱发，也可以由蛋白调控不良引起。改善蛋白平衡似乎可以预防AD，因为唯一与阿尔茨海默氏症负相关的癌症是那些需要并过度产生HSP90蛋白伴侣的癌症。因为蛋白质维持DNA，不好的蛋白质平衡也会引起DNA损伤和突变，进而破坏蛋白质平衡。因此，DNA损伤的增加可能是蛋白质平衡不良和阿尔茨海默病发病机制的生物标记物和驱动因素。该项目有三个核心假设，以预防包括阿尔茨海默氏症在内的与年龄相关的疾病：首先，通过上调保护细胞成分免受损害剂破坏的天然蛋白质，可以使细胞“好于正常”，从而耐受或防止基因组的不稳定和蛋白质毒性。上调这些蛋白质可以产生最良性的药物--我们自己的蛋白质--用于预防和治疗由基因组不稳定和蛋白平衡衰退驱动的疾病，无论遗传或环境疾病的原因是否已知。然而，这些“分子屏蔽”蛋白仍然是未知的，因为没有一种技术足够灵敏，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，还没有任何技术通过上调表达来将天然蛋白质作为“药物”来利用。其次，我假设天然蛋白质可以通过从药理上上调来制造“蛋白质”药物--外源物质可以增加特定蛋白质的产生以保护细胞。最后，我提出了一种灵敏的血压样综合诊断方法，用于AD、癌症和其他年龄相关疾病的疾病前和早期发现，使用DNA损伤标志物。这将确定需要建议的分子屏蔽蛋白化学疗法的个体。 分子屏蔽蛋白可能包括：(1)无处不在的无序抗应激蛋白，它们在与不同大分子相互作用时形成功能屏障，使它们在其他有毒环境中发挥作用；(2)解毒蛋白，使细胞摆脱蛋白质、脂肪和DNA损害剂；(3)产生有毒副产品的途径的阻遏物；以及(4)蛋白质质量控制蛋白。 该项目的目标是-(1)在简单的模式生物大肠杆菌和人类中识别天然的分子屏蔽蛋白；并开创新的技术范例；(2)使用DNA损伤标记物，基于血液的一般诊断，用于阿尔茨海默氏症、神经退行性疾病、癌症和其他与年龄相关的疾病的早期和疾病前检测；以及(3)从天然的人类分子屏蔽蛋白中创造“蛋白质药物”，用于治疗AD和许多医学问题。这些结果可能构成理解一类全新的自然疾病/AD抗性蛋白的基础，检测可能从增强这些蛋白中受益的个人，并将这些蛋白和其他蛋白用作促进健康的药物。

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.