Dreidink Scholars Award
From among those first year medical students participating in the Dreidink Scholars Program from 2015-2019, one student was chosen each year to receive the Dreidink Scholar award, based on the student’s: 1) accomplishments in the lab; and 2) potential for a successful career in translational research.
With the adoption of the JeffMD Curriculum by the medical school in 2018, first-year medical students began performing their research under the Scholarly Activities Program during the academic year. Thus in 2019, the Dreidink Scholar Program transitioned to host aspiring physicians who entered the lab as gap year students. The lab currently hosts six gap year students who participate in a wide range of basic, translational, and clinical research within the Department of Medicine.
The 2019 Dreidink Scholar Award has been awarded to Henry Morelli (recent St. Joseph’s University graduate) and Andrew Lombard (recent William & Mary graduate). Read more about each recipient's endeavors below.
Andrew Lombard, working in the lab of Dr. Raymond Penn, characterized the downstream signaling of the Ovarian Cancer G protein-coupled receptor 1 (OGR1). OGR1 is emerging as a major target for drug development in pulmonary and cardiac therapeutic areas. Primarily studied as a proton sensing receptor, recently studies have identified unique small molecule and peptides that can act as allosteric modulators of OGR1. The discovery of these ligands has significantly aided in characterization of OGR1 receptor biology and identified unique signaling behavior that is agonist-dependent. Specifically, Andrew has systematically characterized the cross-talk between OGR1 and E-prostanoid receptors using airway smooth muscle cells as model cell systems. Andrew has demonstrated that chronic activation of OGR1 with lorazepam (OGR1 agonist) results in a signaling profile that is PKA-dependent. Further, using highly selective inhibitors, Andrew demonstrated that the PKA activation is induced through activation of cyclooxygenases that convert arachidonic acid to prostaglandins. Future studies are focused on comprehensively characterizing the nuances of agonist-specific signaling through OGR1.
Henry Morelli, working in the lab of Dr. Raymond Penn, characterized the agonist-dependent regulation of the Ovarian Cancer G protein-coupled receptor 1 (OGR1). This effort resulted in his first co-authored paper published in American Journal of Physiology. Following completion of the project, Henry began characterizing the differential regulation of contractile signals by E-prostanoid (EP) receptor subtypes in airway smooth muscle cells. These studies were instrumental in demonstrating that signals emanating from activation of distinct EP receptor subtypes could be compartmentalized. Henry also contributed in a minor project with Dr. Ajay Nayak’s laboratory where he helped characterize the allergenic profile of a patient towards snow crab allergens and possible cross-reactivity to house dust mite allergens. This effort has resulted in an abstract which will be presented at the AAAAI meeting to be held in Philadelphia in 2020. Additionally, Henry has mastered other skills such as confocal microscopy and single cell calcium imaging which has resulted in his significant involvement in projects involving other CTM investigators.
Sushrut Shah has worked with Drs. Penn and Deshpande characterizing effects of benzodiazepines in in vitro and in vivo models of airway smooth muscle signaling and function. In vivo models involved examination of mice lacking the Ovarian cancer G-protein receptor 1 (OGR1) gene. He studied the effects of these compounds as a novel therapeutic capable of managing airway resistance and airway remodeling in asthma. Sushrut’s cell-based studies involved characterizing calcium mobilization in human airway smooth muscle cells; this work led to a collaboration with Dr. David Gloriam of Denmark in which novel computer-designed peptides were found to be agonists of the OGR1 receptor. This study was published in the elite journal Cell. Sushrut plans to continue to examine novel OGR1 ligands, derived from those previously discovered, in multiple asthma model systems He is also investigating effects of activation of Beta-2 Adrenergic Receptor (β2AR) by novel agonists. β2AR activation on airway smooth muscle promotes bronchodilation which is a therapeutic goal in asthma and COPD-related diseases. However, activation of the β2AR may also lead to its desensitization and a loss of response to the drug. We have been screening novel compounds that could lead to activation of β2AR while preventing receptor desensitization. Due to his facility with in vivo murine models, Sushrut is significantly involved in multiple projects with other CTM investigators.
Timothy Brandt, Class of 2018
Timothy Brandt, working in the lab of Dr. Tung Chan, helped develop a novel quantitative assay to test whether recently discovered drugs could be used to treat insulin resistance. Resistance to insulin, a hallmark condition in Type 2 diabetes, is typically measured by assessing (reduced) GLUT4 enzyme-mediated glucose uptake in cells. Dr. Chan’s laboratory discovered novels drugs that directly activate the Akt kinase, a key glucose uptake regulator. Tim developed a quantitative assay that uses infrared-on-cell imaging technology and muscle cells in multi-well plates to detect GLUT4 that is exposed to the outer cell membrane. The assay automatically measures signals from thousands of cells and from up to 96 wells at the same time. In contrast, the current standard method requires the assessment of each cell under a microscope magnification, in which accurate quantification is challenging due to photo bleaching, low throughput and observation bias. Tim’s efforts developing a high throughput system for screening drugs regulating glucose uptake are helping pave the way to new diabetes treatments.
Taylor Karl, Class of 2019
Taylor Karl, working in the lab of Dr. Deepak Deshpande, investigated molecular mechanisms of bitter taste receptor (TAS2R) -mediated relaxation of airway smooth muscle cells. Recent studies in human cell and mice have demonstrated that TAS2R agonists are expressed on airway smooth muscle (thus not just on the tongue1), and when activated can dilate airways to improve airflow under conditions of an asthmatic attack. Therefore, TAS2Rs have emerged as promising potential therapeutic targets in the treatment of asthma. Establishing molecular mechanisms by which TAS2R agonists relax airway smooth muscle is a first critical step in exploiting bitter tastants as potential anti-asthma drugs. Taylor investigated the role of actin cytoskeletal reorganization as a potential means by which TAS2Rs cause airway smooth muscle relaxation. In addition, Taylor studied the role of gustducin, a well-known Gi family G protein that is known to mediate TAS2R signaling in taste bud cells. Findings from Taylor’s studies demonstrated that TAS2R-mediated signaling in airway smooth muscle is partly mediated via gustducin. Future studies are needed to ascertain the contribution of additional G proteins in TAS2R signaling in airway smooth muscle cells, and how the novel mechanisms by which TAS2Rs can be exploited therapetically.
Brenda French, Class of 2020
Brenda French, working in the lab of Dr. Sophie Astrof, employed CRISPR technology to knock-in green fluorescent protein (GFP) or other fluorescent proteins at the end of the fibronectin gene, in order to be able to visualize fibronectin in cells throughout embryonic development. Fibronectin is an extracellular matrix protein that functions by binding the surface of cells to help regulate cell adhesion, growth, migration, and differentiation during embryonic as well as post-natal development. Brenda also generated targeting constructs containing GFP, mScarlet, mCardinal, or DENDRA2 as well as guideRNA-containing constructs, and used these plasmids to establish stable primary cell lines such as embryonic fibroblast and cardiac endothelial cells, each expressing fibronectin-fluorescent protein fusions of a different color. Brenda also generated targeting and guideRNA constructs to generate integrin a5-fluorescent protein fusions in animal models. Collectively, her efforts have helped generate novel tools for assessing how interactions between the matrix and cells guide the development of tissues such as the branches of the aorta; understanding these processes is key to preventing development abnormalities that can arise in the vascular system of newborns.
Nathaniel Ash, Class of 2021
Nathaniel Ash, working in the lab of Dr. Shey-Shing Sheu, participated in the phenotypic characterization of cardiac arrhythmias in various genetically modified mouse models. It is known that the most robust Ca2+ uptake in cardiac mitochondria is through mitochondrial Ca2+ uniporter (MCU). However, Dr. Sheu’s laboratory has pioneered the concept that there are additional Ca2+-influx mechanisms including mitochondrial type 1 ryanodine receptor (mRyR1) despite the commonly held belief that MCU is the sole mitochondrial Ca2+-influx mechanism. The discovery that genetic knockout (KO) of MCU in adult mouse hearts leads to minimal adverse phenotypes prompted additional interest into the physiological role of mRyR1 in Ca2+-influx. Nathaniel categorized the phenotypes of inducible cardiac specific MCU KO, mRyR1 KO, and MCU/mRyR1 double KO mice. Additionally, Nathaniel helped to quantify the KO efficiency in the mouse populations used in the study. His experimental results showed that mRyR1 KO and MCU/mRyR1 double KO mice are more susceptible to cardiac arrhythmias and sudden cardiac death. His research helped establish cardiac phenotypes of these mouse models that support the physiological and pathological significance of mRyR1 in the heart. Further studies need to be conducted to elucidate the molecular mechanisms that underlie the observed phenotypes.