Project title “Role of Toll-like receptor-induced short non-coding RNAs in innate immune response.” 

The Kirino lab is focused on understanding the biogenesis mechanism and molecular function of short non-coding RNAs (ncRNAs) and using this knowledge for development of novel biomarkers and therapeutic applications in diseases. 

 

Emad Alnemri, PhD, was recently presented with the Sidney Kimmel Comprehensive Cancer Center 2020 Achievement in Basic Science Award. Dr. Alnemri and his team have provided many fundamental advances in the field of cell death over the course of several decades. His work started with the analysis of caspases and the Apaf1 complex in apoptosis and was followed by analysis of inflammasome complexes and necroptosis. More recently, Dr. Alnemri has studied the regulation of pyroptosis, cell death involving the release of inflammatory cytokines and damage-associated molecular patterns. These recent discoveries have explained the link between apoptosis and pyroptosis, and may ultimately provide the basis for targeted therapies to trigger pyroptosis in melanoma.

Emad Alnemri, PhD, and Andrew Aplin, PhD, were awarded an R01 grant from The National Institute of Health for their project: "Mechanisms of cell death in cutaneous melanoma."

The bulk of funding for research in basic science Departments at Jefferson comes from the National Institutes of Health (NIH). Competition for these federal funds is fierce, with funding rates sometimes as low as 10%.  As a result, scientists spend a disproportionate amount of time writing grant applications, rather than conducting their research and publishing their findings. NIH officials recognize this concern and have attempted to create mechanisms for correcting the situation. One of the most important initiatives that NIH has created is a grant funding mechanism termed the Maximizing Investigators' Research Award (MIRA). As recipients of this award, NIH officials have targeted both junior and established scientists whose stature and track record indicate they deserve an elevated level of freedom from the burdens of grant writing. In short, MIRA recipients are intended to be the scientists whose research is most likely to make transformative discoveries. From the NIH announcement, one of the main intents in creating the MIRA program is to “More widely distribute funding among the nation's highly talented and promising investigators to increase overall scientific productivity and the chances for important breakthroughs”.

At Jefferson, six scientists have recently been awarded MIRA grants, and all six are distinguished members of the Department of Biochemistry and Molecular Biology. These MIRA recipients are Drs. Ya-ming Hou, Jeffrey Benovic, Gino Cingolani, Dmitry Temiakov, Marco Trizzino and Lin Guo. We are fortunate to have these scientists as our colleagues and delighted that the value of their research has been recognized by NIH.

This prize is awarded annually to a member of the Faculty of the Jefferson College of Life Sciences who provides outstanding laboratory mentorship and training that enhances opportunities for interdisciplinary research, teamwork and career development for their trainees, and that bridges the gap between basic and clinical research.

The symposium was a one-day event held at the University of Pennsylvania. This event featured a lecture by Dr. Merry, a prominent CAMB Alum, graduate student talks representing the wide range of CAMB research, poster sessions and alumni career panels.

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Topical Press Release (Thomas Jefferson University)

Anna Pluciennik, PhD, received a 2-year grant from the Gies Foundation to study the molecular mechanisms of CAG triplet repeat instability that is the causal mutation in Huntington’s disease (HD). She proposes to investigate protein assemblies on CAG-extrahelical structures and R-loops in HD patient-derived induced pluripotent stem cells using in vitro and in situ methods. These studies have the potential to identify novel factors that could be targeted for therapeutic modulation of CAG instability in HD.

Philip Wedegaertner, PhD, was awarded a grant from the U.S. Department of Defense for his project: "Targeting the Interaction of G Beta-Gamma and Mutant G Alpha q/11 in Uveal Melanoma."

Jeffrey L. Benovic, PhD, received the 2019 Sidney Kimmel Medical College Research Career Achievement Award. This award is presented to faculty who demonstrate exceptional leadership in, and contributions to, a field of basic and/or clinical/translational research over the span of an academic career.

The 2019 Michael and Melina Pellini Award for Innovation in the Biomedical Sciences was presented to Ya-Ming Hou, PhD, at the May 2019 TJU Awards Program. Each year, this Sidney Kimmel Medical College faculty award is given to one faculty member for the elucidation/description of a specific discovery, technique, or instrument/device that has led to new concepts or approaches to experimentation or patient care.

Gino Cingolani, PhD, received the 2019 Provost Award for Basic Research. This award recognizes a faculty member for significant contribution to their field through basic research.

Dr. James Keen, PhD, received the 2019 Thomas Jefferson University Award for Mentoring. Each year, this award recognizes the exceptional efforts of a senior faculty member who has shown a continued dedication throughout their career to effectively mentor junior faculty to achieve their full potential.

Dr. Keen was also named Sidney Kimmel Comprehensive Cancer Center's Person of the Year for 2018.

Nature Communications Publication (PDF)

Molecular Cell Publication (PDF)

Emad S. Alnemri, PhD, Thomas Eakins Professor of Biochemistry and Molecular Biology, Sidney Kimmel Comprehensive Cancer Center – Jefferson Health (SKCCC), has been named a fellow of the National Academy of Inventors (NAI).

The NAI Fellows Program was established in 2012 to highlight academic inventors and innovators. Election to NAI Fellow status is the highest professional accolade bestowed solely to academic inventors who have demonstrated a highly proli􀃘c spirit of innovation in creating or facilitating outstanding inventions that have made a tangible impact on quality of life, economic development and the welfare of society.

Those elected to the rank of NAI Fellow are named inventors on U.S. patents and were nominated by their peers for outstanding contributions to innovation in areas such as patents and licensing, innovative discovery and technology, significant impact on society, and support and enhancement of innovation.

Anna Pluciennik, PhD, was awarded a grant from the Hereditary Disease Foundation for her project: "Crosstalk between DNA repair pathways in Huntington's disease."

Huntington’s disease is a neurodegenerative disorder caused by an expansion of a CAG repeat tract within the huntingtin gene. The CAG repeat is highly unstable, both intergenerationally and in somatic cells. A growing body of evidence suggests the existence of genetic modifiers of age at onset of the disease. Interestingly, several of these modifiers are genes that encode proteins involved in DNA interstrand crosslink repair and DNA mismatch repair. However, the molecular function of these proteins in somatic expansion of CAG repeats is uncertain; moreover, although these two pathways seemingly have opposing effects on repeat instability, the mechanisms underlying such crosstalk is not understood. Therefore, we propose to isolate and characterize protein assemblies in mouse striatal cells that recognize and process CAG extrusions (the DNA structures that underlie repeat instability). We will also characterize the cell type specific protein assemblies that recognize and process CAG extrusions in human patient iPSC-derived neurons. Modulation of such factors may eventually represent viable therapeutic strategies for the treatment of HD.

Yohei Kirino, PhD, was recently promoted to Associate Professor in the Department of Biochemistry & Molecular Biology.

Peter Ronner, PhD, received the Sidney Kimmel Medical College Faculty Team Achievement Award. This award is given annually and “recognizes the collaborative work of faculty teams leading to innovations or other achievements in clinical care, education, or research.”

Jeffrey L. Benovic, PhD, received the Discovery of the Year Award for Basic Science. The award was presented by Andrew Aplin, PhD, Associate Director of Basic Research at SKCCC, at the 2018 SKCCC Member Retreat held at Citizens Bank Park in Philadelphia. Dr. Benovic and his laboratory have been researching on the mechanisms that regulate G protein-coupled receptor (GPCR) signaling, with a particular focus on the role of GPCR kinases (GRKs) and arrestins. “Because GRKs play a central role in regulating GPCR function, a better understanding of the mechanisms involved in this process provides an opportunity to manipulate this pathway in treating various diseases,” Benovic said.

Gino Cingolani, PhD, received the 2018 Rieders Faculty Prize in Graduate Education. This annual award recognizes outstanding performance by a Jefferson College of Biomedical Sciences faculty member engaged in the education of graduate students at the doctoral or masters level including lecturing in didactic courses, research training in the laboratory setting, or other aspects of student membership.

Dr. Mazo received the Michael and Melina Pellini Award for Innovation in the Biomedical Sciences. This award is given annually to a SKMC faculty member in recognition of exceptional research accomplishments that have “led to new concepts or approaches to experimentation or patient care.” Dr. Mazo’s award broadly recognizes his contributions to the field of epigenetics and is specifically for elucidating mechanisms that connect replication of the genome to gene expression.

Dr. Kirino received the SKMC Early Career Investigator Award for Distinguished Achievement in Biomedical Research. This award is given annually to a faculty member for outstanding research carried out “in basic and/or clinical/translational research within the first ten years of his/her initial faculty appointment.” Dr. Kirino’s award is for elucidating molecular mechanisms used by small regulatory RNAs to control cellular processes.

Dr. Ronner received the SKMC Career Educator Award. This award is given annually in recognition of “outstanding contributions to education in academic medicine both within his/her institution and to education in his/her field over a career.” Dr. Ronner also received the Dean’s Award for Excellence in Education. This award is for faculty who “demonstrate superior effectiveness as a teacher, devote significant time/effort to teaching over a sustained period of time, or for faculty who demonstrate major contributions to an educational course, clerkship or program of training.”

Drs. Jaynes and Winter received the 2017 Professor Fredric Rieders Faculty Prize in Graduate Education. This award is given annually in recognition of “outstanding performance by a JCBS faculty member engaged in the education of graduate students.”

Dr. Wickstrom gave comments on new imagint technology that may revolutionize surgery in FastCompany.

Read the full article here.

Dr. Benovic was a Keynote Speaker at both the September 2017 Temple University Annual Research Day and the September 2017 Department of Pharmacology Retreat at Case Western Reserve University. Dr. Benovic was also a Plenary Speaker at the November 2017 Joint Meeting of Argentine Bioscience Societies.

Koree Ahn, PhD, has been selected as one of five recipients of the 2017 Herbert Tabor Young Investigator Awards for his paper: "Complex interplay of kinetic factors governs the synergistic properties of HIV-1 entry inhibitors."

The Herbert Tabor Young Investigator Award is given to celebrate young authors who contribute top content to The Journal of Biological Chemistry. This award will be presented at the annual ASMBM meeting in April 2018 and will feature a special Spotlight Session.

Emad Alnemri, PhD, Professor, was chosen as a recipient of the Falk Medical Research Trust Catalyst Award for his application entitled: "Role of DFNA5 in the Anti-Tumor Immune Response."

Jeff Benovic, PhD, Professor, and Phil Wedegaertner, PhD, Professor, are part of the Uveal Melanoma Team alongside Andrew Alpin, PhD, Department of Dermatology & Cutaneous Biology, that was awarded the Falk Medical Research Trust Transformational Award.

Dr. Erik Debler received his PhD training in Biophysics with Ian Wilson at The Scripps Research Institute in La Jolla, CA, where he worked on the structure of the IL-2 receptor signaling complex and catalytic antibodies, publishing 12 papers in journals such as Science and PNAS. Erik’s post-doctoral training was with Nobel Laureate Günter Blobel at Rockefeller University, where he published 12 papers on the structure of the nuclear pore complex and on proteins involved in chromatin biology of parasitic organisms, including the human parasite Typanosoma brucei. He discovered bromodomains as novel targets for anti-parasitic treatment. Dr. Debler’s research group focuses on the structure-function relationships of macromolecular assemblies involved in the differentiation and regulation of protozoan parasites of medical importance. Major research themes are elucidating the role of chromatin-associated proteins in the life cycle control of Trypanosoma brucei and targeting these processes to develop novel drugs against parasitic infectious diseases.

Günter Blobel states, “It’s been a great pleasure to have Erik in my laboratory. He is one of the most outstanding and productive young biologists I have encountered in my career. After his numerous contributions towards the atomic structure determination of the Nuclear Pore Complex (NPC), which is the largest and most versatile transport channel in eukaryotic evolution, he has independently and successfully established his own line of research in molecular and structural parasitology. This work beautifully merges his expertise in structural biology with infectious disease biology to further our understanding of host pathogen interactions and shows great promise for development of innovative therapies for a range of protozoan diseases, including malaria, trypanosomiasis, and leishmaniasis. Erik has all the essential qualities to efficiently and successfully run his own lab and become a leader in his field.” Dr. Debler’s office and research laboratory are located on the 8th floor of the Bluemle Life Sciences Building. He can be reached at Erik.Debler@jefferson.edu.

Nature Communication Publication

Dr. Root's team recently published groundbreaking studies on the inhibition of HIV entry that were chosen as an "Editors' Pick" at the Journal of Biological Chemistry.

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In Cell Reports, Mazo's team focused on multipotent hematopoietic progenitor cells (HPCs) that generate all terminally differentiated blood cells and found that the same chromatin-decondensing mechanism is important for their recruitment of lineage-determining transcription factors. CD34-positive HPCs were found to shed the repressive histone mark H3K27me3 just after DNA replication, allowing recruitment of transcription factors that drive cytokine-induced erythroid or myeloid differentiation. More primitive types of HPCs exhibit a very rapid association of nascent DNA with the repressive H3K27me3 histone mark, suggesting that HPCs may utilize special mechanisms of chromatin modification for recruitment of specific transcription factors during the early stages of their lineage specification. Nevertheless, the similarity between the transient disappearance of the same histone mark from nascent DNA of both pluripotent stem cells (ESCs) and multipotent hematopoietic progenitors (HPCs) raises the possibility that "this de-condensation of chromatin occurs irrespective of the induced cell lineage, and thus might constitute a previously unknown general mechanism of induction of differentiation for any cell," according to Mazo. Since the chromatin de-condensing mechanism operates in HPCs, it is likely relevant to gene regulatory changes observed in leukemia cells, which arise when normal hematopoietic cells lose their ability to differentiate properly. Many types of cancer are thought to involve cancer stem cells or other tumor-initiating cells that have lost their ability to differentiate, possibly due to abnormal functioning of this chromatin-based lineage-specification mechanism. Further research on this mechanism may make it possible to manipulate the process, allowing the programming of ESCs or patient-derived stem cells into desired cell lineages for use in disease therapies.

Michael Root, MD, PhD, has been appointed to a Assistant Dean role in the Jefferson College of Biomedical Sciences (JCBS).

Peter Ronner, PhD, Professor, was named AACP Teacher of the Year (2016-2017) from the Jefferson College of Pharmacy. This Jefferson College of Pharmacy student-nominated, Executive Board-selected award is given to a faculty member based on demonstration of student-centered teaching, innovative course development, and effective teaching strategies.

Emad Alnemri, PhD, was recently presented with the Sidney Kimmel Comprehensive Cancer Center 2020 Achievement in Basic Science Award. Dr. Alnemri and his team have provided many fundamental advances in the field of cell death over the course of several decades. His work started with the analysis of caspases and the Apaf1 complex in apoptosis and was followed by analysis of inflammasome complexes and necroptosis. More recently, Dr. Alnemri has studied the regulation of pyroptosis, cell death involving the release of inflammatory cytokines and damage-associated molecular patterns. These recent discoveries have explained the link between apoptosis and pyroptosis, and may ultimately provide the basis for targeted therapies to trigger pyroptosis in melanoma.

Scientific Reports is an online, open access journal from the publishers  Nature.

Acta D is an important structural biology journal that plans to expand its audience to chemists, biochemists and biologists not directly involved in developing/using crystallographic methods. As co-editor for Acta D, Dr. Cingolani will oversee the peer-review process of research papers and thematic reviews mainly dealing with biological motors, structural virology and macromolecular trafficking.

A collaborative study by the laboratories of Jeffrey L. Benovic, PhD, in the Department of Biochemistry & Molecular Biology at Thomas Jefferson University and the Sidney Kimmel Comprehensive Cancer Center at Jefferson, and Dr. Brian K. Kobilka in the Department of Molecular and Cellular Physiology at the Stanford University School of Medicine, provides new insights into a general mechanism regulating signaling from G protein-coupled receptors (GPCRs). Two senior postdoctoral researchers, Dr. Konstantin E. Komolov of the Benovic lab and Dr. Yang Du of the Kobilka lab, share co-first authorship of the new study, which is published in the April 20th issue of Cell.

GPCRs physically span the cell membrane. There they play a central role in enabling cells to respond to extracellular stimuli, including various hormones, neurotransmitters, peptides, and proteins. Stimulation of the GPCR results in activation of cellular G proteins, which in turn modulate the activity of downstream effectors that ultimately control numerous cellular functions, such as cell growth and motility. These signaling events are tightly regulated. One such regulator is a family of proteins called GPCR kinases (GRKs). GRKs bind to and phosphorylate the stimulated receptor, after which a different protein called arrestin then specifically binds to the phosphorylated GPCR. Through this process, GRKs deactivate G protein signaling and activate arrestin-mediated signaling. As Benovic explains, “GRKs play a central role in switching cells from G protein signaling to arrestin-mediated signaling, which is critical in maintaining normal cellular homeostasis.”

In the Cell study, the Benovic and Kobilka groups studied the interaction of a particular GPCR kinase, GRK5, with the β2-adrenergic receptor (β2AR), a cell membrane bound GPCR that is activated (stimulated) by binding to catecholamines such as adrenaline. Their findings reveal key mechanistic features of how these two proteins interact, and how this interaction leads to conformational changes in the GRK that are essential for mediating receptor phosphorylation.

In order to study these interactions within the GRK5/β2AR complex, the researchers first had to replicate the formation of the stable complex, which in cells is associated with the cell membrane. They found that acidic lipids, like the naturally occurring ones found in cell membranes, greatly enhanced the binding of GRK5 to β2AR. They further found that although GRK5 would bind to an inactive form of β2AR, it was binding of GRK5 to an activated (agonist-bound) β2AR that produced a functional complex, one in which GRK5 could phosphorylate β2AR. This suggested that agonist binding created conformational changes in β2AR structure, making it the preferred GRK5 binding partner and enabling formation of a functional GRK5/β2AR complex.

“The molecular model derived from these studies provides important insights into a common mechanism of GRK-GPCR interaction, raising the exciting possibility of exploiting this mechanism to control GPCR signaling,” adds Benovic.

The new findings hold promise for many clinical applications in the future. GPCRs are the target of ~30% of drugs currently on the market, including drugs for the treatment of cancer, cardiovascular and airway disease, as well as various neurological and metabolic disorders. Because GRKs play a central role in regulating GPCR function, a better understanding of the mechanisms involved in this process provides an opportunity to manipulate this pathway in treating various diseases. Another illustration of the importance of understanding the physiological roles of GRK-GPCR interactions in human physiology comes from the report, by another group, that a naturally occurring difference in a single amino acid of the GRK5 protein may enhance phosphorylation of β2AR. Especially intriguing, it has been proposed that this amino acid difference may confer some protection against the development of congestive heart failure for the large percentage of the African American population that have this amino acid difference.

Future plans include dissecting further the interaction of GRK5 with β2AR, using high-resolution structural and imaging approaches such as X-ray crystallography and cryo-electron microscopy, and also analyzing the dynamics of the interaction using approaches such as radiolytic footprinting and double electron electron resonance (DEER) spectroscopy. Studies are also envisioned to explore the broader significance of the newly reported results by examining other interacting pairs of GPCRs and GRKs. Commenting on the long-term goals of this project, Benovic notes that “understanding the structure of a GRK-GPCR complex should help us develop small molecules that enable us to either enhance or inhibit GRK regulation of the receptor, which should have tremendous implications for treating a wide variety of diseases.”

This work was supported by NIH awards R01GM068857 and P01HL114471 (to J.L.B.) and R01GM083118 (to B.K.K.), the Mathers Foundation (to B.K.K.) a Stanford University Terman Faculty Fellowship (to R.O.D.) and the National Research Foundation of Korea funded by the Korean government (NFR-2015R1A1A1A05027473 and NRF-2012R1A5A2A28671860) (to K.Y.C.).

Article Reference: Konstantin E. Komolov, Yang Du, Nguyen Minh Duc, Robin M. Betz, João P. G. L. M. Rodrigues, Ryan D. Leib, Dhabaleswar Patra, Georgios Skiniotis, Christopher M. Adams, Ron O. Dror, Ka Young Chung, Brian K. Kobilka, and Jeffrey L. Benovic, “Structural and Functional Analysis of a β2-Adrenergic Receptor Complex with GRK5,” 2017, Cell 169, 407-421. DOI: 10.1016/j.cell.2017.03.047.