Gene Activation by Innate Nucleophilicity (GAIN): Enabling Precision Stress Defense on Demand
Abstract
The scientific problem, technical approaches, anticipated outcome, and impact on DoD capabilities.The heart of the Navy is the team"" of talented individuals devoted to the core values of honor, courage, and commitment. To assist Navy personnel fulfill their key ro""le in providing credible options for defense of US and its allies~ Naval interests, the US Navy has invested heavily in infrastructu""re, advanced weaponry and prototyping. But in line with the emphasis on the team,the Chief of Naval Operations has identified the n"eed to ~learn faster~ as a core concept of Naval development. This statement reflects the drive to prepare for the sailors of 2025 through enhanced training/education protocols blended with a deeper understanding of the pastoral requirements of individuals to prepare each person for the stresses of Naval life. This proposal seeks to lay the groundwork to strengthen the US Navy with technology" geared to improve the individual~s performance, healing, and ability to fight infection at a specific time. Although idealfor batt""lefield situations, such a technology can be used to overcome immune depletion during times of stress, protect from chemical/biologi""cal attack, and promote resilience to exposure. Indeed, the ability to precondition tomorrow~s military for defense against myriad f""orms ofbattlefield stress (e.g., injury, blasts, toxic chemicals, biological agents, etc.) and ultimately to prime individual perfo""rmance for enhanced military readiness, survival, and endurance, remains an unmet research need (Division 342: Basic Biomedical Prog""ram). There are many methods conceivable to achieve this important goal, but nature has endowed all of us with an awesomebattery of" defense genes that are ready to be unleashed in times of stress. Because stress defense genes are functional in a huge range of rea"l world-relevant situations, remote-controlled triggering of endogenous stress defense is a gateway for maximizing Navy personnel~s"" performance and preconditioning of our forces. Unfortunately, current methods to control theseresponses~genome editing or the use"" of chemical agonists~create permanent genome scars andlack simple control of spatiotemporal precision, and target specificity, res"pectively. Neither approach is satisfactory to upregulate stress response pathways in healthy human subjects and many are in fact irreversible~a condition that is believed to be deleterious. We present a quantum leap in preconditioning for enhanced military readin"ess: we develop, and show the applications of, a programmable small-molecule-based toolkit that hijacks innate redox signals for tur"n-on stress defense in complex vertebrate animals modeled by zebrafish and killfish. Byputting control of stress-responsive protein"s in the realms of precision stress defense, whileleaving the genome untouched, this novel toolkit~administered in a latent form be""fore the timeof need~promises to bestow enhanced stress resistance, performance, and recovery at a userdefinedtime for preconditio""ning. The margins of victory are thin, but we believe that putting control of individual~s stress response in the hands of US Navy p"ersonnel will prove a decisive tool.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- May 05, 2017
- Source ID
- N000141712529
Entities
People
- Yimon Aye
Organizations
- Cornell University
- Office of Naval Research
- United States Navy