The human body is constantly challenged with a wide array of genetic, environmental, or aging-related insults (or stress). These stresses include everything from eating a sandwich to simply getting older. To confront these challenges, the body utilizes a network of stress-responsive signaling pathways that protect cells from various types of insults. These pathways all work through a generalizable mechanism involving the sensing of a defined stress and subsequent activation of signaling cascades that promote protective remodeling of the cellular proteome. As such, these pathways are continuously responding to environmental changes in order to mitigate damage associated with the invariability of the cellular environment. Considering the importance of stress-signaling pathways in maintaining cellular and organismal function, it is not surprising that genetic or aging-associated changes in the activity of these pathways is implicated in the onset and pathogenesis of many different diseases. Our interests primarily focus on defining the pathologic implications of stress-responsive signaling pathways in different diseases with the explicit goal of identifying potential aspects of the endogenous pathways that can be therapeutically targeted to improve outcomes across many disorders. In other words, we are looking to identify ways to ‘hijack’ the body’s own defense mechanisms to prevent pathological imbalances in cellular physiology associated with diverse diseases.
Our primary focus is studying stress-responsive signaling pathways involved in regulating cellular protein homeostasis (or proteostasis) such as the unfolded protein response (UPR), integrated stress response (ISR), and heat shock response (HSR). These pathways function to maintain the integrity of the cellular proteome and prevent the potentially toxic accumulation of proteins that can disrupt cellular physiology. Imbalances in proteostasis are implicated in many different types of disease including neurodegenerative diseases, protein misfolding diseases, metabolic disorders, cardiovascular diseases, and inflammatory diseases. As we focus on defining the specific mechanisms by which stress-responsive proteostasis pathways protect cells against disease-relevant insults, we are identifying new opportunities to mitigate pathologies associated with etiologically diverse disorders. Through these efforts, we are working to develop unique strategies that can potentially be applied widely to treat multiple types of disease in a ‘one-drug:multiple disease’ therapeutic paradigm.
We are developing novel chemical-genetic and pharmacologic approaches to activate stress-responsive proteostasis pathways independent of cell stress. Using these approaches, we can determine the specific importance of a pathway on cellular physiology and define the therapeutic potential for activating this pathway in models of different diseases. We have developed ligand-regulated approaches that are now widely being used by the research community to activate different stress-signaling pathways including the HSR and UPR. Furthermore, we have identified and stringently characterized novel compounds that activate specific protective aspects of UPR signaling. Using these compounds, we are defining their ability to mitigate pathologic imbalances in proteostasis associated with multiple different types of disease including systemic amyloid diseases, neurodegenerative disorders, eye diseases (with the Lin lab at UCSD), cardiovascular diseases (with the Glembotski lab at SDSU), diabetes (with the Saez lab at Scripps), and many more. Specific compounds found to be broadly beneficial across these diseases are being further developed in collaboration with the Kelly lab at Scripps.
Apart from our development of strategies to mitigate pathologic imbalances in proteostasis, we are also interested in improving our understanding of how stress-responsive signaling pathways regulate different aspects of cellular physiology, most notably mitochondrial proteostasis and function. We have an active program specifically focused on determining how stress-responsive proteostasis pathways, such as the ISR, regulate diverse aspects of mitochondrial biology including proteostasis, morphology, and energy metabolism. Moreover, we have established a highly productive structural collaboration with the Lander lab at Scripps directed towards defining a molecular basis for mitochondrial proteostasis regulation. Through these efforts, we are revealing the underlying mechanisms responsible for regulating mitochondria in response to stress and identifying new opportunities to mitigate pathologic mitochondrial dysfunction through the targeting of stress-responsive proteostasis pathways.