Kim Sharp studies protein and nucleic acid structure and function using theoretical methods, computational and computer graphics tools. He currently splits his time between research, teaching, writing and BMB Graduate Group activities. Kim's current research includes work on development of virtual drug design tools and the mechanism of viral genome packing. In his role as BMB Graduate Group Chair, he is updating the graduate biostatistics curriculum and teaching Ph.D students Bayesian Statistics. Kim’s book, “Entropy and the Tao of Counting: A Brief Introduction to Statistical Mechanics and the Second Law of Thermodynamics,” will be published by Springer in January 2020. In his spare time, he collaborates with Franz Matschinsky on translating Ludwig Boltzmann’s papers on statistical mechanics intoEnglish.
Vera Moiseenkova-Bell is an Associate Professor with appointments in both the Department of Systems Pharmacology and Translational Therapeutics and the Department of Biochemistry and Biophysics. She is also a Faculty Director for the Electron Microscopy Resource Laboratory and Beckman Center for Cryo-Electron Microscopy.
The Moiseenkova-Bell laboratory is focused on understanding structure and function of Transient Receptor Potential (TRP) channels which have been implicated in a diverse range of cellular processes, including pain sensation, neuronal development, cardiovascular and renal pathophysiology, and cancer. Dr. Moiseenkova-Bell and her team utilize cryo-electron microscopy to determine the structural basis of TRP channel activation, inhibition and desensitization mechanisms. Structural information on TRP channels and their interaction with agonists/antagonists at the molecular level will establish a structural framework to enhance our understanding of their function at the molecular level, whereby improving therapeutic strategies and drug design.
Franz M. Matschinsky
Franz M. Matschinsky, now on the way to retirement in 2021, continues to collaborate with a group of colleagues here at Penn and other institutions in the US and abroad. His efforts are focused on unraveling the molecular and physiological basis of glucose homeostasis in health and its defects in disease with particular emphasis on role of the glucose phosphorylating enzyme glucokinase. This enzyme, first discovered by Dr. Matschinsky, functions as the glucose sensing element of cells in the endocrine pancreas, the liver, the gut, the pituitary and neurons of different brain centers regulating fuel homeostasis. Over 600 inhibitory and activating mutations of have been discovered in this enzyme in humans. To combat these disease-causing mutations, allosteric glucokinase activator molecules are currently being assessed for their therapeutic potential in type II diabetics.
Bohdana Discher is a research associate professor in the Department of Biochemistry and Biophysics. The Discher laboratory utilizes biophysical and chemical tools to design synthetic water-soluble and membrane proteins. These non-natural proteins are based on a simple, functionally transparent 4-alpha-helical scaffold, which makes them an ideal test bed for ligand binding or electron transfer and catalysis. These proteins have been exploited to study light harvesting, magnetic field sensing in bird navigation and for blood substitute development. Their future promise lies in the development of rapid optical reporting of voltage sensing for neuroscience and mitochondrial research as well as for redox sensing within living cells to study metabolism.
The Murakami lab seeks to understand the mechanisms of RNA polymerase II transcription activation in response to stress and its regulations in the context of chromatin. The lab is also interested in the mechanism of nucleotide excision repair (NER). In particular, we focus on the mechanism of how a set of factors serve dual functions in NER and transcription and how they are regulated. In all of these projects we use primarily structural (cryo-EM and cross-linking mass spectrometry) and biochemical approaches to dissect the architecture and function of the macromolecular complexes we study.
Greg Van Duyne
The Van Duyne laboratory studies the mechanistic biochemistry of site-specific recombination and retroviral integration. Site-specific recombinases such as phage integrases and resolvases are widely used in genome engineering and in vitro DNA applications. Cre recombinase, an enzyme that the Van Duyne laboratory has studied extensively, is a well-known example. The integrase from HIV, which inserts a cDNA copy of the viral RNA into the host genome, is the focus of much of our current work. The laboratory uses a broad range of structural, biochemical, and cell-based approaches to study these systems. Our HIV program involves close collaborations with researchers from Penn and from the pharmaceutical industry to study the mechanism of action of a new class of integrase inhibitors.
Rahul Kohli is a physician-scientist with appointments in both the Department of Medicine and the Department of Biochemistry and Biophysics. The Kohli lab is focused on the study of enzymes that modify and mutate DNA, given the central role that genome dynamics play in epigenetics and in host-pathogen interactions. These processes are open to interrogation by enzymology and chemical biology approaches. The lab also aims to harness the biotechnological or therapeutic potential of DNA altering enzymes and pathways, with applications that include new sequencing methodologies, targeted genome editing, and combating the evolution of antibiotic resistance. Dr. Kohli is passionate about supporting pathways that meld fundamental science and medicine, and in this spirit, also serves as an Associate Program Director for Penn’s MD/PhD program.
Mitch Lewis has long been a leader in understanding the biophysical parameters that determine how proteins respond to metabolites and regulate transcription. In recent years, the Lewis lab has used this knowledge to generate tunable transgene expression in gene therapy vectors. This work has tremendous promise to reduce toxicity and improve our ability to use gene therapy to cure disease. Dr. Lewis’s interest in metabolic regulation of transcription is also manifest in his commitment to teaching medical students, as he serves as director of the Metabolism course that is central to the first year medical school curriculum.
The Wilusz lab aims to reveal new insights into how RNAs are generated, regulated, and function. By combining high-throughput approaches with detailed biochemical studies, the laboratory has revealed new mechanisms controlling transcription, pre-mRNA processing, and translation of many protein-coding genes. Ongoing efforts are focused on circular RNAs, which have covalently linked ends, and a novel role for the Integrator complex in transcription termination. Congratulations to two postdoctoral fellows in the Wilusz lab who have successfully obtained NIH Pathway to Independence (K99/R00) Awards in the past year!
Kristen Lynch is Chair of the Department and a Professor of Biochemistry and Biophysics with a secondary appointment in Genetics. Kristen’s laboratory studies regulation of RNA processing, namely alternative splicing and polyadenylation, and how these processes are controlled during immune responses. For example, a recent study focused on the role of alternative splicing in host-viral interactions. Additional areas of interest are how signaling pathways influence the activity of RNA binding proteins, the variation of splicing in cancer and in T cell biology, and the coordination of splicing with polyadenylation and epigenetics. Kristen also oversees the Penn RNA Group.
S. Walter Englander
Walter Englander is the emeritus Gershon-Cohen Professor of Biophysics and Medical Science and a member of the National Academy of Sciences and The American Academy of Arts and Sciences. His lab led the development of the hydrogen exchange field for protein biophysical studies, discovered the role of cooperative foldon units in protein structure and folding, developed the defined pathway model to explain how proteins fold, and invented and developed the leading-edge technology of hydrogen exchange mass spectrometry (HX/MS). His lab is actively involved in protein folding studies and in the function of large energy-driven protein machines like heat shock protein 104.
WELCOME to our newest member of the faculty, Dr. Yi-Wei Chang! The Chang Lab is devoted to understanding biology from a structural perspective. Based on the notion that the best way to understand the function of a molecule is to understand its structure in its native environment, the Chang lab utilizes Electron Cryotomography (ECT), an emerging powerful cryo-electron microscopy imaging technique, to study the structure and mechanism of macromolecular nanomachines directly inside cells. ECT reveals not only native conformations and assemblies of the nanomachines as they are conducting functions, but also their distribution, orientations and interactions to other cellular components – thus enabling studies of Structural Cell Biology and Molecular Sociology. We are excited to have Dr. Chang and ECT as part of our growing cryo-EM community.
Ben Garcia is the John McCrea Dickson M.D. Presidential Professor of Biochemistry and Biophysics, as well as vice-chair of the Biochemistry and Molecular Biophysics Graduate Group and Director of the Quantitative Proteomics Resource Center. The Garcia Lab utilizes high-resolution mass spectrometry to explore cellular signaling, epigenetic mechanisms and chromatin regulation; with particular interest in understanding how protein and nucleic acid modifications regulate nuclear processes. Recent discoveries include understanding the structural dynamics of histone tails, uncovering connections between histone acetylation in metabolism, and identifying lncRNAs in ant brains. The Garcia lab also is a leader in the development of mass spectrometry methods, enabling new applications of mass spectrometry throughout the scientific community.
The Marmorstein laboratory studies the molecular mechanisms of protein post- and co-translational modification with a particular focus on protein acetylation and phosphorylation and chromatin regulation. The laboratory uses a broad range of molecular, biochemical and biophysical research tools centered on macromolecular structure determination. The laboratory is particularly interested in gene regulatory proteins and their upstream signaling kinases that are aberrantly regulated in cancer and other age-related disorders, and the use of high-throughput small molecule screening and structure-based design strategies towards the development of protein-specific small-molecule probes to be used to further interrogate protein function and for development into therapeutic agents.
Sergei Vinogradov's research is focused on the development of optical probes for biological microscopy and imaging. The laboratory has long-standing interest in metalloporphyrins, which can be used as sensors for oxygen, pH, metal ions and other environmental parameters of biological systems. Two-photon phosphorescence lifetime microscopy (2PLM) of oxygen, developed by the lab, is now broadly used in neuroscience and stem cell biology. Recently, the group theoretically predicted a new class of porphyrins with exceptionally high two-photon absorption cross-sections, and using them developed probes for 2PLM with 100 times higher performance. The current focus is on exploration of higher order optical non-linearity, such as in three-photon absorption, to gain deeper insight at the energy metabolism in the brain.
Ben Black, newly promoted Professor, and his team are answering some of the most pressing questions in chromosome biology, such as: How does genetic inheritance actually work? How was epigenetic information transmitted to our parents? And can building new artificial chromosomes help us understand how natural chromosomes work?The Black lab has made seminal discoveries regarding the physical basis for how CENP-A-containing nucleosomes epigenetically mark and maintain centromere location on the chromosome. Recently they have also discovered how amplified centromeric DNA repeats act as selfish elements in female meiosis to explain rapid centromere evolution.
Congratulations to Jim Shorter, one of the newly promoted Professors in the Department. The Shorter lab is a leader in the study of protein aggregation and disaggregation. His laboratory uses techniques ranging from biophysics to yeast genetics to identify novel ways to dissociate toxic protein phases that are common in many neurodegenerative diseases. In a recent exciting study published in Cell, Dr. Shorter and colleagues discovered that nuclear-import receptors can dissociate toxic phase separated states of several RNA-binding proteins connected to neurodegenerative diseases. These findings open the way to urgently needed therapeutics for amyotrophic lateral sclerosis and frontotemporal dementia.
Kathy (Fange) Liu
Welcome to the newest faculty in the Department, Dr. Kathy Fange Liu! Dr. Liu joins us from U Chicago, where she was a post-doctoral fellow with Chuan He and Tao Pan. She brings expertise in enzymology and RNA modifications to the Department. The rapidly growing Liu Lab studies the roles of RNA epigenetics in the regulation of human energy homeostasis using a broad spectrum of research tools including of RNA biochemistry, structural biology, and Next-Gen sequencing. Topics of study in the Liu Lab currently include: regulation of mRNA and tRNA modifications; identification and function of new types of modifications in messenger RNA; and the relationship between tRNA modification, tRNA fragmentation and disease.
Gideon Dreyfuss is a Howard Hughes Medical Institute Investigator and the Isaac Norris Professor of Biochemistry and Biophysics. The Dreyfuss Lab focuses on RNA-binding proteins and small nuclear ribonuclear protein complexes (snRNPs), their roles in the life of messenger RNAs (mRNAs) and their links to disease. Recently his group uncovered a new gene regulation mechanism in metazoan cells termed Telescripting, in which the U1 snRNP suppresses cleavage and polyadenylation signals, thereby protecting nascent transcripts from premature transcription termination. Telescripting is crucial for full-length mRNA synthesis, especially for large genes, and also determines mRNA length. A recent study from the lab demonstrates the importance of Telescripting for regulating size-function-stratified genomes.
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