Research Opportunities At Geisinger Commonwealth, students have the opportunity to conduct research under the mentorship and guidance of distinguished faculty. Research projects developed by faculty research mentors who are seeking research assistants are described below. Students do not need substantial experience as these research activities and mentors provide a unique educational opportunity. Geisinger Commonwealth has multiple organized research opportunities including the Summer Research Program for students entering their 2nd year of medical school at Geisinger Commonwealth. Undergraduate students from affiliated institutions are also encouraged to apply for research assistantships. Geisinger Commonwealth has affiliation agreements with many area colleges including but not limited to the University of Scranton, East Stroudsburg University, Marywood University, Philadelphia University of the Sciences, Wilkes University and the University of Pittsburgh. Application Instructions: Review the research project and identify a research project that interests you. A brief introduction of key areas and current research is listed below. Click on the researcher’s name to link to their faculty page. Submit a resume and cover letter to SPlaney@tcmc.edu The faculty research mentor will review your application materials and respond to you. Dr. John Arnott’s lab: Osteoporosis is a major health care problem that disproportionally afflicts the elderly, women and underrepresented minorities. In the U.S., ~10 million people have osteoporosis and ~34 million more have low bone mass or osteopenia. Osteopenia leads to increased incidence of bone fracture that alone costs ~$19 billion annually. Thus, there is a critical need for developing and improving drugs and treatments for the prevention and clinical management of osteopenia and osteoporosis. Dr. John Arnott’s research focuses on regulation of skeletal development and the molecular mechanisms that control bone formation. Currently, we are characterizing how the novel bone growth factor, connective tissue growth factor (CTGF/CCN2), regulates osteoblast differentiation and function. We are also working on identifying druggable targets that control CTGF expression in osteoblasts, particularly its regulation by other bone growth factors. Developing an understanding of the growth control mechanisms in bone, and the identification and characterization of the mechanisms that regulate osteoblast differentiation and function, will help identify new therapeutic targets to enhance bone formation in patients with clinically significant bone loss. Dr. Michael Bordonaro’s lab: The primary focus of Dr. Michael Bordonaro’s research is to understand how modulation of the Wnt signaling pathway influences decisions of cell growth vs. cell death in colorectal cancer (CRC) so that more effective preventive and/or therapeutic approaches against this disease may be developed. Wnt signaling is normally important for cell growth and differentiation. However, mutations in this cellular pathway that result in deregulated Wnt activity cause abnormal colonic cell growth that eventually leads to cancer. Although moderate Wnt signaling activity induces cell growth, extremely high levels of Wnt signaling can cause cell death. Butyrate, a product of dietary fiber, increases Wnt signaling to an extent that promotes CRC cell death; this may in part explain the protective role of fiber against CRC. Therefore, we are interested in studying: (a) the changes in Wnt-specific gene expression caused by butyrate that results in cell death, (b) the mechanisms by which CRC cells can become resistant to butyrate and how this resistance can be overcome, (c) how various transcriptional factors and other cell signaling pathways interact with Wnt signaling to mediate the effects of butyrate, and (d) how aberrant Wnt signaling can be targeted for gene therapy approaches against CRC. Dr. Youngjin Cho’s lab: The actin filament associated protein 1(AFAP1) plays an important role in the organization of the actin cytoskeleton and the localization and activation of c-Src, a prominent proto-oncogene implicated in normal physiology as well as cancer progression. Utilizing an AFAP1 knockout mouse model where the expression of AFAP1 is ablated in every tissue, we have found that AFAP1 is necessary for normal lipid metabolism and trafficking. Mice deficient in AFAP1 have defects in mobilizing triglyceride-enriched vesicle to properly produce milk and display excess lipid accumulation in the liver. The current focus of Dr. Youngjin Cho’s lab is to elucidate the exact mechanism by which AFAP1 contributes to lipid metabolism, as the knowledge gained from the research directly applies to our understanding of various human diseases including non-alcoholic hepatic steatosis. Dr. Jess Cunnick’s lab: The cellular actin cytoskeleton is vital for numerous cellular processes including migration, proliferation and differentiation. Dr. Jess Cunnick’s lab studies how an actin filament‐associated protein, AFAP1, and interacting cell signaling proteins, contribute to the regulation of cellular processes that depend on the integrity of the actin cytoskeleton. One major group of AFAP1 interacting proteins is the Src kinase protein family. The prototypical member of this family is the proto‐oncogene c‐Src, whose activity is enhanced in a number of cancers. AFAP1, through its interaction with c‐Src and other proteins, has been shown to be involved in the formation of cellular protrusions that facilitate cancer cell invasion. However, Src family proteins have also been shown to regulate a large number of physiological processes, including glucose and lipid metabolism. Our lab has developed a mouse model that no longer expresses AFAP1, a knockout mouse. Using this mouse model our lab is investigating the mechanism by which AFAP1 and Src kinase protein partners regulate actin cytoskeleton dependent cellular processes and physiological processes such as glucose and lipid metabolism. The knowledge gained from our research will provide a better understanding of cancers where the disturbance of c‐Src‐mediated cellular processes might directly contribute to cancer progression and also signaling pathways that contribute to metabolic diseases, such as diabetes. Dr. Jeffrey Holt’s lab: Developing novel approaches for early genetic screening of hereditary breast or ovarian cancer is the current focus of Dr. Jeffrey Holt’s research. Because cancer patients have a high risk of a second malignancy and their relatives with mutations have an increased risk of breast and ovarian cancer, it is important to know which breast and ovarian cancer patients harbor BRCA1 and BRCA2 mutations. These subsequent cancers would be discovered early or prevented if widespread genetic screening was available; moreover, recent data indicates that BRCA hereditary cancers respond to targeted therapies such as cisplatinum and PARP inhibitors. We have been able to correctly identify more than 95% of breast and ovarian cancer samples as either hereditary or non-inherited types using an antibody-based tissue immunostaining method to identify BRCA2 hereditary cancers. This approach visualizes protein truncation by showing with immunohistochemistry (IHC) that the N-terminus is present but the C-terminus is absent. We are also developing other strategies to identify specific populations of individuals who can be readily screened for breast or ovarian cancer. Dr. Raj Kumar’s lab: Understanding the relationships between steroid hormone receptor (SHR) function and structure is the current focus of Dr. Raj Kumar’s research. Intrinsically disordered (ID) sequences within proteins are unstructured regions that are associated with cell signaling and human diseases. Steroid hormone receptors (SHRs) are ligand-dependent intracellular transcription factors and are essential regulators of key physiological processes as well as important therapeutic targets in several diseases including inflammation, hormone-dependent cancers, osteoporosis, and cardiovascular disease. Despite the fact that full receptor activity requires a concerted effect of both AF1 and AF2 activation domains, and that AF1 is critical for cell and target gene specificity of SHRs, the current design of selective receptor modulators (SRMs) for clinical uses is primarily based on their effects on AF2, thereby missing the whole SHR signaling spectrum. A better understanding of how AF1 mediates cell/tissue and target gene specific responses is essential for improved therapeutic targeting of SHRs. Our lab is investigating to identify targets that act outside of the AF2 pocket, which could complement or replace AF2-based existing SRMs. Dr. Darina Lazarova’s lab: Colon cancer prevention, detection, and therapy are the current focus of Dr. Darina Lazarova’s research. (1) Early, non-invasive diagnostics. We are investigating novel approaches to detect colonic tumors by exploiting the ability of cancer cells to induce specific markers when exposed to dietary supplements. (2) Prevention. Cell heterogeneity within a tumor has not been taken into account in cancer prevention strategies. Thus, we are evaluating the contribution of several signaling pathways to colon cancer cell survival after exposure to specific diet-derived metabolites. These studies may allow for formulation of dietary recommendations that decrease the risk of colon cancer. (3) Therapy. Cancer cell heterogeneity allows tumors to evade the effects of anticancer agents and is a major problem in cancer therapy; therefore, we are investigating the use of combination drug therapy to overcome the robustness of the colonic tumors. Because the incidence of colon cancer in the Northeastern Pennsylvania region exceeds the national average, our goal is to test our hypotheses regionally by obtaining data on the dietary habits of patients with colonic tumors and by employing basic science methodologies. Dr. Jun Ling’s lab: Studies in Dr. Ling’s lab focus on cancer molecular biology, specifically on the molecular mechanisms of breast cancer development and biomarker discovery in prostate cancer. The goal of these studies is to identify new targets/pathways for the development of new diagnostic and therapeutic strategies. The detailed research projects are concentrated on the following areas: a) Regulation of cancer development by mRNA translation. The regulation of mRNA translation is closely involved in cancer initiation and progression. A number of translational initiation factors (eIF) function as proto-oncogene (e.g., eIF4E and eIF4G) or tumor suppressor (e.g.IF4E-binding protein/4E-BP). The focus in our lab is to investigate how eIFs are regulated by cell signaling, therefore leading to the modulation of global and selective gene expression during the process of cancer progression. b) Roles of PAK2 and PIM1 kinase in cancer development and drug resistance. Our research is concentrated on PAK2 kinase, a small G-protein activated kinase functioning as a stress-activated kinase that can be cleaved by caspase 3 during apoptosis. Another kinase in our study is PIM1 kinase, an oncogenic kinase with proliferative and pro-survival functions. By studying this “yin-yang” regulation of kinases, we expect to identify new mechanisms contributing to cancer progression and drug resistance. The other focus in Dr. Ling lab is on Biotechnology; currently we are working on a biosensor technique combined with chemical engineering to generate a non-antibiotic approach to treat antibiotic-resistant infections. Dr. William McLaughlin’s lab: Members of Dr. William McLaughlin’s laboratory study the large scale elucidation of protein structure to function relationships. Connections between diseases, health conditions, proteins, and medications are made with attention paid to their quality and completeness. Query systems are developed which may take as input a disease or a health condition. The output is the relevant proteins and putative therapeutics. Novel predictions of protein biological functions and disease associations of proteins are also derived. The laboratory plays an integral part of the NIH project called Protein Structure Initiative: Biology, which has the goal of structurally and functionally characterizing proteins. Students gain training in the fields of structural bioinformatics and translational bioinformatics. Dr. Sonia Planey’s lab: The signaling networks under the control of the ZDHHC2 gene that are important to cancer and bladder disease are the current focus of Dr. Sonia Planey’s research. ZDHHC2 encodes the palmitoyl acyltransferase enzyme, DHHC2, which is deleted in many types of cancer. Its absence in cells is highly correlated with metastasis; therefore, investigating the function of this gene in established cancer cell lines will allow us to better understand its role in preventing metastasis. DHHC2 modifies specific cellular proteins with a lipid called palmitate. One substrate of this enzyme is cytoskeleton-associated protein 4 (CKAP4) which is a cell-surface receptor for antiproliferative factor (APF)—a small biomolecule that potently inhibits cell growth and is thought to cause a painful, chronic bladder disorder called interstitial cystitis (IC). Using cellular-based models, molecular biology techniques, and novel biochemical approaches, our goal is to gain a more detailed understanding of DHHC2-mediated palmitoylation of CKAP4/p63 and its effects on APF-mediated signaling so that we can identify novel drug targets for IC and cancer as well as develop a diagnostic test for IC. Dr. Gregory Shanower’s lab: Investigating the role of histone modifications in stem cell maintenance and development is the current focus of Dr. Gregory Shanower’s research. grappa (gpp) is the Drosophila melanogaster ortholog of Dot1L, a human gene encoding an enzyme that methylates lysine residues on Histone H3. Methylation of Histone H3 on lysine 79 via Dot1L is directly linked to active gene transcription, maintenance of telomeric silencing, and regulation of cell cycle progression. However, to date very few studies have examined the role this histone methyltransferase plays in developmental processes. Our evidence suggests that gpp regulates a major signal transduction pathway involved in cell cycle regulation in the fly. This signaling pathway is involved in multiple aspects of carcinogenesis in human cells. However, the transcriptional regulation of this signaling pathway is not well defined in either flies or humans. Therefore, we aim to examine gpp’s role as a transcription factor regulating this pathway using Drosophila melanogaster as a model system. Further, our lab is investigating how chromatin modifying enzymes regulate: 1) signal transduction pathways in epithelial cells, 2) cellular polarity of epithelial cells, and 3) stem cell and stem cell niche biology. Dr. Ying Ju Sung’s lab: Chronic pain is a disabling condition that is associated with many diseases and from which millions of patients suffer but fail to obtain relief. Identifying the signals and the genes expressed during the cascade of events resulting from nerve injury to primary sensory neurons is the current focus of Dr. Ying Ju Sung’s research. Our lab has elucidated a pathway that sensory neurons use to inform the brain that an injury has occurred, and activating this pathway alters the electrical property of neurons. A key enzyme in this pathway is called PKG (Protein Kinase G). PKG acts like an on/off switch—if the switch is left on and uncontrolled, it results in a persistent activation of the pathway, causing pain. In collaboration with colleagues from Columbia University, we have developed two lead compounds that are highly potent and selective against PKG. Therefore, these compounds have tremendous potential for use in treating chronic pain. Using various animal models of pain, we aim to evaluate the analgesic efficacy of these compounds. Research and Community Engagement The Geisinger Commonwealth Research Team sponsored the following programs by inviting students on site to participate in research education and coordinated simulated research activities, presenting information regarding medical school and research opportunities as well as attending planning meetings and executing events for the individual organizations. Pennsylvania Junior Academy of Science (PJAS) PJAS is a statewide organization sanctioned by the Pennsylvania Academy of Science whose mission is to provide a forum where secondary students can conduct scientific research and present the results of that research on both a local and state level. The Commonwealth of Pennsylvania is divided into twelve PJAS regions. In 2009, we established the Geisinger Commonwealth/PJAS fellowship in collaboration with Dr. Clay LaCoe, the regional director of PJAS Region 2. Together, we saw an opportunity for students in the region to experience and understand what it means to be a working scientist and to gain access to a network of professionals who could provide mentorship about science/medical career opportunities. The fellowship is awarded annually to a small and select group of PJAS students as part of a competitive process that involves the completion of an essay and personal interview during the annual PJAS regional competition. Awardees spend two days in the summer at Geisinger Commonwealth and engage in hands-on learning with faculty and medical students in our state-of-the-art research facilities. To date, we have hosted 28 fellowship awardees from high schools throughout Northeastern Pennsylvania. Biomedical Career Linking Academy As part of their week long investigation into careers in the healthcare industry students toured Wayne Memorial Hospital (WMH) and Geisinger Commonwealth School of Medicine (Geisinger Commonwealth). The students were presented with information on a variety of occupations within the Biomedical and Healthcare Industry. Wayne Pike Workforce Alliance Wayne Pike Workforce Alliance, the Community Education Council of Wayne and Pike Counties, is founded on the concepts of community and collaboration. The group helpts to identify, create and provide educational opportunities that build the area’s workforce. Girl STEM Conference The conference seeks to inspire middle-to-high school girls to pursue STEM- related fields (Science, Technology, Engineering, Math). Girl STEM features interactive seminars with professional women, hands-on workshops, and open forum discussions. Geisinger Commonwealth Community Garden Club The Community Garden Club educates Geisinger Commonwealth students, faculty and staff about the influence that nutrition has on health, organic gardening and sustainable growing. The Club reaches out to the community through various community organizations by providing fresh produce, education on nutrition and gardening, and therapeutic gardening.