Research

Overview - Stress Response, Proteostasis, and Diseases:

from molecular mechanisms to physiology

Gene expression, proteostasis and the oxidative stress response

Oxidative stress is one of the most prevalent types of environmental stresses and underlies the development and progression of many diseases. In response to oxidative stress, eukaryotic cells must reprogram gene expression at multiple levels to support their viability. Our lab investigates the underlying mechanisms by which gene expression is regulated at the transcriptional and translational levels in response to stress.  We are also very interested in understanding how the small protein modifier ubiquitin controls protein synthesis and degradation during stress. Dysregulation of these pathways can lead to cellular dysfunction and death, which is the causation of several diseases. Our lab uses an array of cellular and molecular biology tools, proteomics, structural biology, and next generation sequencing to tackle these questions.

Cracking the Ubiquitin Code in Health and Diseases

 

The ubiquitination system acts through a cascade of enzymes that controls most cellular functions. Yeast encodes in its genome ~120 genes for ubiquitin enzymes and it is estimated that humans might encode > 1000, which could represent up to 5% of the entire human genome! Mutations to these enzymes are associated to several human diseases such as Parkinsons' (E3 Parkin), cancer (BRCA1), Fanconi anemia (FANCD2), and other intellectual disabilities such as the Nascimento Syndrome (E2 UBE2A). However, the molecular mechanisms by which the dysregulation of these enzymes affect cellular physiology remains unclear.  To resolve this ubiquitination code, our lab invests in genome-wide methods (e.g. CRISPR screens) to identify and characterize ubiquitin enzymes important for cellular physiology, as well as molecular tools to understand their cellular role. Our ultimate goal is to dissect these unique pathways and develop ubiquitin-based therapies to support cellular health.

Funding

Our research is supported by:

PI: National Institute of General Medical Sciences (NIGMS) R35 MIRA award - R35GM137954

Dissecting the roles of ubiquitin in translation control (2020-2025)

 

 

 

 

 

PI: Chan Zuckerberg Initiation - Science Diversity and Leadership Award

Deciphering the Functional Ubiquitinome in Health and Disease (2022-2027)

 

 

 

 

 

PI: Duke Office for Research & Innovation  - SPARK Award

Integrating metabolomics and proteomics to understand ubiquitination in metabolism and stress resistance (2022-2024)

 

 

 

 

 

PI: National Institute of Environmental Health Sciences (NIEHS) R21 award - R21ES032964

Characterizing New Redox Roles for Protein Ubiquitination in Human Cells (2022-2024)

PI: National Institute of Environmental Health Sciences (NIEHS) K99/R00 award - R00ES025835

Defining the roles of ubiquitination during the environmental stress response (2015-2021)

 


Collaborations

 

National Institute of Allergy and Infectious Disease (NIAID) R01 award - R01AI155512

Regulation of RIG-I signaling and viral immune evasion by ufmylation (PI: Stacy Horner, co-PI: Gustavo Silva)