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

点击翻译按钮获取中文摘要

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.