Research Newsletter Winter 2019 by Rutgers New Jersey Medical School

NJMS.RUTGERS.EDU

RESEARCH

ROUNDUP highlighting our researchers and their outstanding achievements

Winter 2019

Welcome Aboard

ane Parker, PhD, recently joined the NJMS Center for Immunity and Inflammation and the NJMS Department of Pathology and Laboratory Medicine where he studies the interaction between bacterial pathogens and the innate immune system. He earned a PhD from Monash University in Melbourne, Australia. Much of his research focuses on the type I and type III interferon signaling pathways, how bacterial pathogens can activate the pathways, and how they influence inflammation and bacterial clearance during infection. His work with the bacterial species Staphylococcus aureus, Acinetobacter baumannii and Streptococcus pneumoniae is funded by an R01 grant from the National Heart Lung and Blood Institute.

essa Bergsbaken, PhD, joined the Center for Immunity and Inflammation (CII) and the NJMS Department of Pathology and Laboratory Medicine in 2017. She earned her PhD from the Department of Microbiology at the University of Washington. She continued her training at the University of Washington, where she focused on tissue-resident memory CD8+ T cell populations that develop in the intestinal tissue in response to local infection. Bergsbaken identified the mechanism by which T cells localize to areas of infection within the intestinal tissue, and the role of specific inflammatory cytokines in supporting the differentiation and long-term persistence of tissue-resident memory T cells. Her long-term goal is a better understanding of the mechanisms of T cell differentiation and maintenance in the intestine and other mucosal sites, and determining the unique functions of tissue-resident memory lymphocyte subsets during secondary infection. Her lab is utilizing these findings to improve CD8+ T cell function in the context of colorectal cancer immunotherapy. Bergsbaken’s findings have been published widely, most recently in Cell Reports, Volume 19, April 2017, with co-investigators Michael Bevan and Pamela Fink. Her current work is funded by a National Cancer Institute Career Development Award (K22) from the NIH and Feldstein Medical Foundation.

osuke Kumamoto, PhD, joined NJMS IN 2017 as Assistant Professor of Pathology and Laboratory Medicine and a member of the Center for Immunity and Inflammation. He earned his PhD in pharmaceutical sciences from the University of Tokyo, and completed postdoctoral training in the Department of Immunobiology at Yale University. His research focuses on the role of dendritic cell subsets in regulating inflammation and adaptive immunity, with a particular focus on type 2 immunity in the skin. His current study of dendritic cells is supported by an R01 grant from the NIH/National Institute of Allergy and Infectious Diseases.

ataki Douglas, MD, PhD, recently joined the faculty as Associate Professor and Director of Translational Research in the Department of Obstetrics, Gynecology and Women’s Health and a member of the Center for Immunity and Inflammation. Douglas is an obstetrician/gynecologist with subspecialty training in reproductive endocrinology and infertility and doctoral training in molecular, cellular, and developmental biology. She earned her MD and PhD degrees from Yale University School of Medicine, and subsequently completed her residency in Obstetrics and Gynecology, and a fellowship in Reproductive Endocrinology and Infertility, at Columbia University Medical Center/ NewYork-Presbyterian Hospital. She then joined the Columbia University faculty as an attending reproductive endocrinologist. Douglas is a board-certified reproductive endocrinologist who combines patient care with basic/translational research. As an NIH funded researcher, Douglas focuses on achieving a better understanding of molecular mechanisms that underlie uterine vascular development early in pregnancy at the time of formation of the placenta. She utilizes unique animal models to study interactions between the uterine decidual vasculature and trophoblasts, while simultaneously seeking to validate these models in terms of human disorders of pregnancy. Her objective is to improve the diagnosis and treatment of infertility and common pregnancy complications, including early miscarriages, intrauterine growth restriction, and preeclampsia.

ongfang Liu, PhD, recently joined the Institute of Infectious and Inflammatory Diseases, and the Department of Pathology and Laboratory Medicine, at NJMS. He earned his PhD in immunology in 2005, and did postdoctoral work on natural killer (NK) cells at the NIH from 2005 to 2011. He subsequently became a senior research scientist at Ragon Institute of Massachusetts General Hospital, MIT, and Harvard, where he worked on HIV-specific cytotoxic T lymphocyte (CTL) dysfunction, with a focus on the role of PD-1 on CTL immunological synapses (IS). In 2012, he joined Baylor College of Medicine, and in 2015, moved to the Houston Methodist Research Institute, where he was promoted to associate professor. Liu is studying the biology of human cytotoxic lymphocytes (including NK and CTKs) using molecular, biochemical, and single molecule imaging strategies. He applies live cell imaging and biophysical approaches to studying the signaling and vesicular traffic at the immunological synapses, with a focus on immunobiology of chimeric antigen receptor T and NK cells (W. Xiong, et al., 2018, Molecular Therapy), and human lymphocyte dysfunction in chronic infectious diseases, such as HIV and HIV-related malignancies. His projects focus on: the mechanism controlling the bidirectional vesicular traffic at cytotoxic and inhibitory immunological synapses; the role of the Crk family of proteins in the immune response; and immunotherapy for HIV and HIV-related malignancies. He explains: “Highly active antiretroviral therapy (HAART), which is invaluable, does not halt the growth or proliferation of non-Hodgkin’s lymphoma or cure HIV. Patients live longer, only to succumb to a malignancy for which few weapons are available. This calls for the development of innovative therapies.”

ason Weinstein, PhD, joined the NJMS Center for Immunity and Inflammation and the Department of Medicine on August 1. He earned his PhD from the University of Florida, where he worked on understanding the mechanisms that underlie the generation of autoreactive B lymphocytes in lupus/ chronic inflammation mouse models. He completed a post-doctoral fellowship and stayed on to become faculty in the Section of Rheumatology at Yale University School of Medicine. His current research focuses on understanding how the signals from CD4+ T cells that regulate B cells in the chronic autoreactive state compare to those in an acute infectious response, and how these adaptive immune cells malfunction in the germinal center response in autoimmunity.

uijuan Hu, PhD, recently joined the Center for Immunity and Inflammation and the Department of Anesthesiology as an associate professor. She came to NJMS from Drexel University College of Medicine where she was an associate professor in the Department of Pharmacology and Physiology. Her laboratory aims to understand the mechanisms underlying the development of chronic pain; and also to identify novel drug targets and drug candidates for the treatment of chronic pain. Her research has concentrated on the role of store-operated calcium channels (SOCs) in pain plasticity. In addition, Hu is interested in investigating whether maternal pain exposure alters pain behavior in offspring. Her laboratory employs a variety of approaches in its current studies, including behavioral tests, patch clamp electrophysiology, live-cell imaging, and biochemical and molecular biology.

homas Dick, PhD, joined the Public Health Research Institute of NJMS in 2017 as associate professor of medicine and director of antimicrobial drug discovery. He earned his PhD from Heidelberg University, Germany, and completed his post-doctoral fellowship at the Institute of Molecular and Cell Biology in Singapore. His lab focuses on the molecular mechanisms of antibiotic resistance and applying this knowledge to the discovery of new antibacterials, primarily targeting TB and lung disease caused by Non-Tuberculous Mycobacteria (NTM). He holds a Visiting Professorship in the Department of Microbiology and Immunology at the School of Medicine, National University of Singapore, where in prior years he served as Director of the BSL3 Core Facility and associate professor. He also established and led the TB disease area at the Novartis Institute for Tropical Diseases, Singapore.

For more information on our researchers/faculty, please visit CII and i3D. 2

Awards & Accolades

Published & Printed

he Board of Governors of Rutgers awarded the Krieger Klein Endowed Chair in Alzheimer’s Disease and Neurodegeneration Research to Luciano D’Adamio, MD, PhD, professor of pharmacology, physiology, neuroscience and neurology at NJMS, in April. He will lead the newly formed Alzheimer’s Disease Research Center, which will focus on basic and translational research. The researcher is recognized for identifying key molecular mechanisms of age-related neurodegeneration in Alzheimer’s disease. D’Adamio came to NJMS from the Albert Einstein Cancer Center in New York and has published more than 90 peer-reviewed articles in prestigious scientific journals.

recent study, led by David Alland, MD, professor and chief of infectious disease, Department of Medicine, and NJMS associate dean for clinical research, and Roberto Colangeli, PhD, assistant professor of medicine, was published in The New England Journal of Medicine, August 30, 2018. The study demonstrates that TB treatment outcomes can be predicted, but not by current methods. According to Alland, “Approximately 5 percent of patients with TB that can be effectively treated have a relapse after six months of first-line therapy. Approximately 20 percent have a relapse after four months of short-course therapy.” The NJMS study demonstrated that testing the Mycobacterium tuberculosis bacteria before an individual begins treatment can identify those at high risk of relapse in most cases, as well as identifying those who can be treated for four instead of six months and those who should be treated for more than six months to achieve a cure. These results could translate into dramatic savings for public health programs and better treatment results for those infected with TB. The study was funded by the National Institute of Allergy and Infectious Diseases.

eresa L. Wood, PhD, (Grant ID : R37NS082203, Award: $1,526,092, Title: The role of MTOR signaling in oligodencrocyte differentiation and CNS myelination) NJMS professor and Rena Warshow Endowed Chair in Multiple Sclerosis in the Department of Pharmacology, Physiology and Neuroscience, and her collaborator, Wendy Macklin, PhD, University of Colorado, are winners of the Senator Jacob Javits Award in Neuroscience, administered by the National Institute of Neurological Disorders and Stroke. Wood’s research focuses on understanding signaling pathways that regulate differentiation of glial progenitor cell populations in the central nervous system that are important for developmental myelination and to orchestrate remyelination in the adult brain and spinal cord following injury or demyelination. The U.S. Congress established this award, given to scientists for their superior competence and outstanding productivity, to honor the senator, who had amyotrophic lateral sclerosis (ALS) and was a strong advocate for research in brain and nervous system disorders.

mariliz Rivera, PhD, assistant professor, Department of Pediatrics, and a member of the Center for Immunity and Inflammation (CII), has focused her research on how the immune system recognizes and fights the fungal pathogen Aspergillus fumigatus. Most recently, studies from her lab uncovered a novel factor involved in the regulation of the immune defense against fungal infection. These findings on the importance of type III interferons (IFN-Lambdas) in the body’s response to fungal pathogens were published in the article, Type III interferon is a critical regulator of innate antifungal immunity, Science Immunology, October 6, 2017. The studies were done in collaboration with Sergei Kotenko, PhD, professor, Department of Microbiology, Biochemistry and Molecular Genetics, a member of CII, and co-discoverer of type III interferons. Fungal infections have increased in incidence over the past decades and are associated with high mortality rates. Aspergillus fumigatus is one of the significant causes of invasive fungal infections in susceptible patient populations, and can also cause allergies, respiratory diseases, and bloodstream infections. Antifungal medications are often ineffective and fungi have also evolved resistance to current drugs. The identification of host factors, such as interferons, as critical activators of host immune cells could pave the way for the development of new therapies aimed at boosting host immunity.

MAJOR GRANTS The Research Office at Rutgers New Jersey Medical School is dedicated to facilitating the research endeavors of the NJMS community. Our mission is to provide assistance in identifying funding opportunities, preparing proposals and managing awards. The following pages share details about a few of the recent grants at Rutgers New Jersey Medical School.

New Grant to Study Helminths

ince arriving at NJMS, Mark C. Siracusa, PhD, (Grant ID: R01AI131634, Award: $2,477,000, Title: Protective and pathologic functions of macrophages induced by helminths) a Chancellor Scholar and assistant professor in the Center for Immunity and Inflammation and the Department of Medicine, has been working to help develop a better understanding of the factors that control the initiation and magnitude of helminth-induced inflammation. Elucidating these pathways will form the basis for developing new therapeutic strategies to not only treat helminth infections, but also other inflammatory diseases such as allergies and asthma. He was recently awarded a $495,400 grant entitled Protective and Pathologic Functions of Macrophages Induced by Helminths. Multiple studies have demonstrated an essential role for lung macrophages in promoting protective immunity and initiating wound healing following infection, but the specific macrophage populations and accessory cells that promote these pathways remain unknown. This project will combine hypothesis-driven experiments and state-of-the-art methodologies to investigate how tissue- and monocyte-derived lung macrophages cooperate with accessory cells to promote host protective responses following a helminth challenge. These goals will be addressed by employing the collective intellectual and scientific resources of the Siracusa and Gause laboratories, and the results of these studies will increase understanding of how pulmonary macrophages are programmed in the context of acute inflammation. In 2016, Siracusa also received a multi-year, $397,500 NIH grant entitled Innate Immune Regulation of Helminth-Induced Inflammation, which will help support his immune system research through 2020. His recent findings identifying a new therapeutic target to treat allergic inflammation were recently published in the Journal of Experimental Medicine. 4

Worm Research

orms and their damaging effects on human health are finally getting their due. Unbeknownst to many, worms (also called helminths) are a major cause of deadly disease in the developing world. George Yap, PhD, (Grant ID: R01AI134040, Award: $2,935,210, Title: Induction of effector lymphocyte lethargy by helminth coinfection) NJMS associate professor of medicine and a member of the Institute for Infectious and Inflammatory Diseases (i3D), and William Gause, PhD, NJMS senior associate dean of research, director of i3D, and professor of medicine, recently received a $3 million R01 grant from the NIH to study how worms prevent vaccinations from bolstering the immune system. When worms travel through tissues in the body, they damage the tissues; and the damaged tissues release “danger signals” that can trigger immune responses. It’s extremely difficult to eliminate parasitic worms, Gause says. The worms are rampant in parts of the world where sanitation is poor and are thought to infect 1.5 billion people. While drugs to eliminate helminths are available, people are often re-infected after an infection clears; and over-treating populations for worm infections may lead to the development of drug-resistant strains. The ultimate goal of this research is to discover how CD8 cells are impaired by worms and how to re-engineer vaccines to circumvent worm-damage. This team also received a second NIH grant of $511,711, titled “Genesis of Defective Effector Lymphocytes in the Helminth Coinfected Host.” Gause and George Hasko, PhD, are conducting a tandem study on worm infection. This five-year, $3.2 million study, also awarded by the NIH, will examine how the immune system actually detects the helminth infection, and then becomes activated to protect against the parasite while weakening the very immune components that protect humans against microbes, such as those causing TB. The combined results of the two NIH-funded studies will provide scientific data on the role of these worms in damaging immunity.

Fighting One of the World’s Deadliest Infections

urnima Bhanot, PhD, (Grant ID: R01AI133633, Award: $2,117,715, Title: Development of inhibitors of P.falciparum cGMP dependent protein kinase (PIPKG) for malaria chemoprevention) Associate Professor of Microbiology, Biochemistry and Molecular Genetics, was awarded two NIH grants totaling over $2.5 million, which she and her team will use to discover novel drugs to combat malaria. One of the deadliest infections in the world, malaria is estimated to kill more than 400,000 people yearly. Malaria is caused by Plasmodium parasites that are transmitted to humans by mosquito bites. There is no available vaccine against malaria. Current antimalarial drugs are expensive, have significant side effects, and are challenged by the appearance of drug-resistant Plasmodium strains. In addition, few of the current antimalarials block the first step of malaria--the infection of the liver by Plasmodium. Bhanot and collaborators at the Rutgers School of Pharmacy and Montclair State University will synthesize potent inhibitors of Plasmodium’s PKG enzyme, and test their ability to block infection of the liver by the parasite. 5

Vitamin D in the Limelight

ylvia Christakos, PhD, (Grant ID: R01DK112365) NJMS professor of microbiology, biochemistry, and molecular biology, has been awarded more than three decades of uninterrupted NIH funding for her research on the mechanisms by which inadequate vitamin D contributes to osteoporosis. She and Michael Verzi, PhD, a Rutgers faculty member, won a $582,981, RO1 NIH grant entitled, Nutrigenomics of Intestinal Vitamin D Action. They will use a genomic approach, coupled to physiology studies in novel mouse models, to test their hypothesis that the proximal and distal segments of the intestine each have unique regulatory pathways controlling vitamin D receptor expression and vitamin D action. The most important function of vitamin D is the regulation of intestinal calcium absorption, which is critical for bone health. Their preliminary data reveal an essential role for VDR, a gene that ultimately allows the body to respond appropriately to vitamin D, in the distal intestine. Their research may suggest new approaches to prevent bone loss in those at high risk.

New Shared Instrumentation Grant

ong Li, PhD, (Grant ID: S100D02J047) NJMS associate professor of microbiology, biochemistry and molecular genetics, and director of the Center for Advanced Proteomics Research (CAPR) at NJMS, was recently awarded a one-year, $1,092,346 shared instrumentation grant from the NIH. The grant will fund the purchase of a high-end mass spectrometer (the Thermo Scientific Orbitrap Fusion Lumos mass spectrometer) coupled with a Dionex UltiMate 3000 RSLCnano HPLC system, to meet the rising demand for high-performance proteomics instrumentation on the Newark campus. With the new Lumos MS, Rutgers researchers and collaborators will be able to enjoy the new features that are not available on instruments currently in the core facility: 1. the ability to conduct both accurate and sensitive quantifications of proteins and post translational modifications (PTMs); 2. the ability to perform efficient top-down proteomics, a revolutionary mass spectrometry technology for the analysis of intact proteins and the identification of proteoforms, including proteolytic products, sequence variants, and combinations of PTMs; 3. the ability to selectively detect and quantify low-abundance peptides in highly complex biological matrices; and 4. the ability to map new PTMs and identify challenging peptides. The new equipment will be installed at the Center, where scientists will use it for NIH-funded projects, and other investigations, on neuronal signaling pathways, cancer, and cardiac dysfunction.