Pursuing the Therapeutic Potential of the SUMOylation System by Characterizing the Mechanisms That Regulate SUMO Levels in the Cell
Abstract
This proposal is directly responsive to the Fiscal Year 2019 Peer Reviewed Medical Research Program Topic Area of Emerging Infectious Diseases as it pursues the development of broad-spectrum approaches to combat both seasonal influenza virus strains as well as newly emerging flu strains with pandemic potential. Due to the effects produced by influenza virus in the human body, this proposal is also responsive to the Topic Areas of Respiratory Health, Lung Injury, and Acute Lung Injury. Although influenza viruses are commonly viewed as human viruses, there are very few influenza strains that are capable of infecting humans. In contrast, a large variety of influenza strains are maintained in aquatic birds, i.e., ducks, geese, swans, waders, and gulls. Occasionally, some of these strains gain access to domestic fowl and, from there, make their way into humans, producing episodes of human infections frequently associated with alarming disease outcomes. These emerging influenza strains could eventually gain the ability to be transmitted from human to human and therefore constitute a pandemic threat. Our current antiviral weapons appear rather inadequate because they target structural components of the virus that are continuously changing due to the genetic variability of these viruses. It is therefore essential to develop new strategies to combat these viruses. We postulate that a system that exists in all cells of our body, known as the SUMOylation system, provides the body with a potential strong weapon against influenza virus. The activity of the SUMOylation system is rapidly increased when cells are infected with the flu virus and, if this increase is large enough, the virus can’t multiply and the infected cells are protected. The SUMOylation system is also rapidly increased by other types of stress, including extreme heat, extreme cold, lack of oxygen, and limited blood flow, and in every case the increased SUMOylation protects the cell, keeping it alive. Therefore, it is not surprising that SUMOylation may also provide protection against viral invaders. The long-term goal of our studies is to develop small molecules capable of triggering rapid increases in the activity of the SUMOylation system, so that its protective effects may be used to treat the flu and other conditions that trigger cellular stress, such as heart attacks and strokes. To accomplish this, it would be very helpful to know how the SUMOylation system is regulated. We hypothesize that a process known as alternative splicing, which produces small but meaningful changes in the templates used to make proteins, may play a central role in regulating the activity of this system. To explore this possibility, we propose to measure the abundance of the different templates that code for the SUMO proteins (the central players in the SUMOylation system) under different types of stress conditions. We also propose to study how changing the proportion of those templates affects the ability of the SUMOylation system to respond to stress and characterize the activity of new forms of the SUMO proteins that up to now had remained unknown. These studies will greatly enhance our knowledge on how the cell regulates the activity of the SUMOylation system and could potentially lead to the development of new methodologies to increase SUMOylation. In turn, this could provide new approaches for the treatment of conditions that trigger cellular stress in our bodies, such as other viral infections and cardiovascular accidents.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010088
Entities
People
- German Rosas-acosta
Organizations
- United States Army
- University of Texas at El Paso