Research Interests

Stress and Apoptosis in Drosophila development

Some cells are programmed to experience stress or undergo death as part of their developmental fate. Healthy cells can initiate the apoptosis program by activating genes that are dedicated to killing themselves, which helps the body to eliminate superfluous or potentially dangerous cells. Likewise stress in specific subcellular organelles can occur as part of a cell’s differentiation program, which in turn help those cells mature the affected organelles and assume specific function. After the completion of development, apoptosis and stress response pathways are essential to maintain the integrity of adult cells, and defects in these mechanisms underlie a wide variety of diseases in humans, which include cancer, neurodegenerative diseases and diabetes. In my laboratory, we primarily use the genetic and cell biological tools of Drosophila to understand the molecular basis of apoptosis regulation and cellular stress response to advance our understanding of development and disease.

Our work on apoptosis regulation centers around caspases, which are cystein proteases that acquire activity in response to upstream pro-apoptotic signals. As active caspases play a central role in the execution of apoptosis, regulators of caspases exhibit strong effects on a cell’s decision to live or die. In my laboratory, we have largely focused on those genes that regulate apoptosis through ubiquitin-mediated protein degradation. Our research over the years has unraveled the role of protein ubiquitination in apoptosis at multiple levels, including those that help degrade anti-apoptotic members (Ryoo et al., 2002) and pro-apoptotic factors (Shapiro et al., 2008). Ongoing research aims to identify novel mechanisms of apoptosis regulation and assess their possible roles in Drosophila disease models.

Our second research program is aimed at understanding how endoplasmic stress (ER-stress) is regulated in Drosophila.  ER-stress is frequently caused by misfolded protein overload in the ER, which activates signal pathways and quality control mechanisms that help reduce such stress. One of the key signaling pathways is mediated by xbp1 mRNA splicing, which causes a frame shift during its translation to generate an active xbp1 transcription factor. Among xbp1’s transcriptional target includes ER chaperones and other ER quality control genes that help reduce the level of stress in the ER. To study the cellular control of ER stress, we have developed a molecular sensor for ER stress, xbp1-EGFP, designed to express EGFP in frame only when it has undergone mRNA splicing in response to ER-stress (Ryoo et al., 2007). In addition, we have developed ER-stress assays where misfold-prone protein expression is forced into developing tissues of the fly, causing developmental abnormalities as a consequence. A screen for suppressors of this phenotype have revealed genes that recognize misfolded proteins in the ER for degradation, anti-apooptotic proteins, as well as those that affect intracellular signaling. Many of these genes affect the course of retinal degeneration in the Drosophila model for Retinitis Pigmentosa, where a mutation in the rhodopsin-1 gene dominantly triggers age-related retinal degeneration similar to the human condition. We are currently characterizing these genes trying to reconstruct the sequence of molecular events that occur to protect cells against ER stress in Drosophila.