Sharon Rosenberg, MD, is a second-year fellow in our Pulmonary and Critical Care Medicine fellowship, is a second-year fellow in our Pulmonary and Critical Care Medicine fellowship program. Sharon is working with Drs. Scott Budinger and Gokan Mutlu within the division and Drs. Kevin Weiss and Ruchi Gupta in the Institute for Healthcare Studies to investigate the effects of particulate matter (PM) on childhood asthma prevalence and exacerbations. Dr. Rosenberg’s research focuses on the asthma prevalence pattern in Chicago neighborhoods and aims to determine association with PM. She will also investigate association of PM levels within neighborhoods with childhood asthma hospitalizations. She will utilize hospitalization data from the Illinois Department of Public Health and PM data from the Environmental Protection Agency (EPA) and Multi-Ethnic Study of Atherosclerosis (MESA) Air study. Dr. Rosenberg is currently pursuing a Masters in Clinical Investigation at Northwestern University.

Sheren Fakhran, MD, is a second year fellow in the Pulmonary and Critical Care Fellowship program. She is currently working with Gokhan Mutlu on investigating the effects of particulate matter on asthma. Ambient particulate matter air pollution is known to significantly contribute to asthma morbidity. Her research will focus on the mechanism by which particulate matter elicits worsening asthma symptoms. The research will be done using both in vitro and in vivo mouse model. She will specifically look at whether there is down regulation of beta-adrenergic receptors in the airways after exposure to either direct instillation or inhalation of particulate matter.

Krisitina Kligys, PhD, is a postdoctoral fellow working in Dr. Jonathan Jones’ laboratory. Dr. Kligys’ research focuses on dissecting the mechanism by which cells move in a directed fashion. Results from their laboratory have suggested that signaling by the β4 integrin to the actin severing protein cofilin, in a Rac1 dependent manner, promotes migration of epithelial cells in a linear trail. Although loss of β4 integrin expression does not prevent cell motility, cofilin activity is decreased, and the pattern of epithelial cell migration is impaired, such that cells now move in circular arrays. Recently, Dr. Kligys has shown that cofilin activity is regulated by the slingshot family of phosphatases in epithelial cells and that inactivation of cofilin leads to changes in actin cytoskeleton organization, loss of cell polarity and assembly of aberrant arrays of laminin-332. The activity of the slingshot family of proteins has been shown, by others, to be regulated by 14-3-3 protein binding. Results from our current research suggest that the 14-3-3/slingshot protein interaction is dependent on the level of Rac1 activity and that the association between 14-3-3 proteins and slingshot proteins plays an important role in mediating the migration patterns of epithelial cells. These data, in combination with previous work, suggest a novel mechanism in which α6β4 integrin signaling via Rac1, 14-3-3 proteins and slingshot family members regulates cofilin activation, cell polarity and matrix assembly, leading to specific epidermal cell migration behavior.

Elise Alexandra Kikis, PhD, is a postdoctoral fellow working in Dr. Richard Morimoto's laboratory. Her research is associated with protein misfolding, a fundamental problem in biology and human disease associated with many diseases of protein conformation. They have developed genetic models in C. elegans to address the role of protein context as a modifier of an imbalance in protein homeostasis. Specifically, she will resolve whether the signature polyglutamine tract found in disease-causing proteins is the sole determinant of disease or whether, via the interaction with unique subsets of cellular factors, the protein context in which the polyglutamine tract is embedded modulates aggregation/toxicity. To address this, they will develop models in the genetically tractable C. elegans. These models will be characterized for protein aggregation dynamics using live-cell imaging, and for toxicity of the respective disease-causing proteins via behavioral assays. Dr. Kikis will use the new models to conduct high-throughput RNAi screens for the identification of modifiers of protein aggregation in the HD and SBMA/Kennedy's Disease models. The results of these screens will be comparable to each other and to previous screens for modifiers of polyQ-YFP aggregation. Consequently, she expects to identify a core set of modifiers that act on all polyQ-containing proteins, in addition to factors, which act in a sequence context-specific manner to modulate the aggregation of particular disease-causing proteins. Stress signaling and protein homeostasis is essential for all cells and in particular for those such as the alveolar epithelium and diseases of protein folding are prominent in an understanding of the molecular events in folding and clearance of CFTR. She is also interested in establishing how changes in the composition of the atmosphere, specifically how increases in CO2 affect biological processes in genetic model systems such as C. elegans.

Colleen Snyder is a pre-doctoral fellow in Dr. Navdeep Chandel’s laboratory. Colleen is researching the pathway underlying nitric oxide (NO)-induced apoptosis. NO is an essential signaling molecule for cellular maintenance, and consequently dysregulation of this molecule contributes to diseases such as stroke and myocardial infarction. Colleen has demonstrated that NO triggers cell death through the intrinsic apoptotic pathway since Bax/Bak double knock out or Caspase-9 deficient cells are protected from NO-induced cell death. Additionally, Bax-/-/Bak-/- cells reconstituted with either Bax or Bak undergo NO-induced cell death. How Bax and Bak are activated to initiate apoptosis in response to NO remains an area of study. Bcl-xL is an antiapoptotic protein that functions upstream of Bax/Bak and must be negated to allow Bax/Bak dependent cell death. Bcl-xL protein levels remain stable in response to NO treatment and therefore may be negated through protein-protein interactions. Currently, Colleen aims to identify proteins that bind and inhibit Bcl-xL to allow Bax/Bak dependent cell death in response to NO. In addition to Bcl-xL, Bax and Bak are regulated by the proapoptotic Bcl-2 family of proteins. Colleen will determine if these proteins play a role in NO-induced cell death. Understanding the signaling pathway underlying NO-induced cell death may provide an effective therapeutic strategy for the treatment of NO associated pathological conditions.

Rebecca Daugherty is a pre-doctoral graduate student working with Dr. Cara Gottardi to understand the regulation of beta catenin-mediated transcription. Overexpression of the actin-binding protein, alpha catenin, can antagonize beta catenin signaling in a variety of cell types, including A549 lung cancer cells, and, given that alpha catenin is an important tumor suppressor protein, Rebecca is attempting to characterize the transcription-regulating function of alpha catenin as well as elaborate mechanisms regulating alpha catenin protein stability. Rebecca has shown that alpha catenin accumulates in the nucleus of HEK293T in response to Wnt3a stimulation and binds to the transcriptionally active, hypophosphorylated form of beta catenin. Preliminary chromatin immunoprecipitation experiments have also demonstrated that alpha catenin can bind to the Wnt-regulated c-myc promoter, suggesting that alpha catenin inhibits transcription at the level of the promoter. In addition to characterizing nuclear alpha catenin, Rebecca has mapped the domains of alpha catenin required for transcription regulation and has identified a domain encompassing amino acids 279-687, a region previously shown to bind proteins such as vinculin, alpha actinin, and afadin. Subsequent experiments will examine whether alpha catenin cooperates with these proteins to regulate beta catenin function. Finally, alpha catenin protein is downregulated in A549 cells in an EGFR-dependent manner. In an attempt to establish a mechanism regulating protein stability, Rebecca has found that suppression of casein kinase 2 (CK2), an enzyme regulated by EGFR, leads to the accumulation of alpha catenin in A549 cells. Serine 641 of alpha catenin is targeted by CK2 and future experiments will examine the significance of this residue for alpha catenin protein stability.