Faculty and Research
The faculty members of the Department of Biochemistry comprise an ideal blend of biochemists, biophysicists, and chemists who collaborate to identify and improve bioactive molecules for such purposes as fighting cancer, parasitic disease, and other neurodegenerative disorders.
The Department’s annual retreat in New Braunfels, Texas, provides a relaxing atmosphere for members to keep up with each others’ work.
The Chen Lab studies the synthesis and design of medically important small molecules. We develop new methods and strategies for natural-product synthesis, and design small molecules that modulate cellular functions. We seek to advance the technologies for small-molecule synthesis and develop new drugs for treating cancer and immune diseases.
The Chuang Lab focuses on structure, function, and regulation of mitochondrial protein machines and their clinical ramifications. We currently use structure-based design to develop a new generation of small-molecule inhibitors specific for mitochondrial pyruvate dehydrogenase kinases (PDKs) and branched-chain α-ketoacid dehydrogenase kinase (BDK). These kinase inhibitors have shown good promise in promoting oxidation of glucose and of branched-chain amino acids, while reducing lipogenesis in animal models for obesity and type 2 diabetes.
The De Brabander Lab focuses on the synthesis of complex molecular architectures. Synthetic targets include both designed and naturally occurring substances with novel structural features and interesting biological function. We also develop novel methodology toward functionality found in complex natural products. We integrate our synthetic program with molecular pharmacology, biochemistry, and cancer biology. Our group also collaborates to discover novel small-molecule activators of programmed cell death, glucagon suppressors for the treatment of diabetes, antitumor agents that selectively target tumor-derived neuronal stem cells and colon cancers with APC truncations, anti-trypanosomal agents for the treatment of African Sleeping Disease, and V-ATPase inhibitors and their role in cancer and as anti-viral agents.
The main theme of our research is the application of synthetic and bioorganic chemistry to problems of biochemical and medicinal relevance. Several of our projects involve collaborations with laboratories specializing in pharmacology, physiology, internal medicine, nephrology, and oncology at UT Southwestern and other institutions.
The Gilles-Gonzalez Lab focuses on understanding the mechanisms by which living organisms respond to oxygen and other physiological gases. Since demonstrating that FixL is a histidine protein kinase that is switched on and off by a sensory heme, we have established that FixL belongs to a much broader family of sensors with varying heme-binding folds and enzymatic activities. Members of this family include diguanylate cyclases, c-di-GMP phosphodiesterases, and transcription factors. Our recent work on the Mycobacterium tuberculosis oxygen sensors DevS and DosT has led us to propose that they control this bacterium’s dormancy, which afflicts about two-thirds of the world’s population. Simultaneously, our studies of Escherichia coli sensors have led us to propose that an O2-regulated complex in this bacterium, which includes diguanylate cyclase DosC and cyclic-di-GMP phosphodiesterase DosP, is a dedicated RNA-degrading machine.
The Hammer Lab uses genetically engineered mouse models to investigate the mechanisms by which liver homeostasis is regulated in the face of hepatic injury or pertubations in hepatic cell fate. One area of investigation addresses the role of p53 in sub-lethal hepatic failure using mice that either lack hepatic expression of ribosomal protein S6 (rpS6) or express a dominantly active form of p53. A second area revolves around the mechanisms by which constitutive activation of wnt/-catenin and notch.
The Kohler group develops chemical biology methods targeted toward study of glycosylated molecules. Using a metabolically incorporated photocrosslinking analog of sialic acid, we investigate functions of sialylated host molecules in bacteria infection. We also study the role of glycosylation in nucleocytoplasmic transport, making use of a photocrosslinking analog of the O-GlcNAc modification.
The goal of the Liszczak lab is to reconstitute complex biological signaling networks in highly controlled environments. Specifically, we are interested in understanding how aberrant nuclear protein post-translational modification activities contribute to genetic diseases such as cancer. To accomplish this, we integrate chemical biology tactics, including protein semi-synthesis, with biochemical and genetic approaches to better understand the role that protein modifications play in transcription regulation and genome integrity. Ultimately, we seek to identify and characterize novel, therapeutically vulnerable mechanisms underlying enzyme activation, substrate specificity, and the downstream effects of protein modifications.
The McKnight Lab divides its efforts and interests between studies of P7C3, a neuroprotective chemical, and studies of intrinsically disordered “low complexity” (LC) sequences associated with DNA and RNA regulatory proteins. We hypothesize that these LC sequences reversibly polymerize in a manner that facilitates sub-cellular organization. The later ideas point toward a “solid-state” conceptualization of information transfer from gene to message to protein.
Research in the Mendelson lab focuses on molecular mechanisms involved in developmental and hormonal regulation of key genes and signaling pathways in perinatal biology and female reproduction. We study genetic and epigenetic mechanisms in differentiation of the placental syncytiotrophoblast and surfactant-producing cells of fetal lung, as well as mechanisms underlying the maintenance of myometrial quiescence during pregnancy and the initiation of uterine contractility leading to term and preterm labor. Our studies support an important role of maturation of the fetal lung and synthesis of lung surfactant in the timing of birth.
We study the biochemistry of trypanosome and malaria parasites, with a focus on enzymology, structural biology, and drug discovery. Our target pathways are pyrimidine biosynthesis in Plasmodium falciparum and both polyamine biosynthesis and nucleotide metabolism in Trypanosoma brucei.
The High Throughput Screening Core Facility focuses on the discovery and pre-clinical development of new small-molecule therapeutics. The core also supports identification and characterization of novel biological targets and pathways for therapeutic intervention in cancer, neuro-degeneration, metabolic diseases, parasitic infections, and other disease states.
The Ready Group focuses on chemical synthesis, including medicinal chemistry, natural products synthesis, and development of methodology. We are broadly interested in the synthesis of biologically active small molecules, especially complex anti-cancer agents, from marine and bacterial sources and of synthetic compounds discovered through unbiased high-throughput screening.
The Roth Lab focuses on discovering drug-like small molecules with interesting biological properties and then determining the mechanisms by which they act. With chemists and pharmacologists at UT Southwestern, we improve the potency and other properties of these chemicals so they become useful leads for developing therapeutic drugs.
The Siegwart Lab aims to discover and define the critical physical and chemical properties of synthetic carriers required for therapeutic delivery of small (e.g. ~22 base pair miRNA) to large (e.g. ~5,000 nucleotide mRNA) RNAs. Their long-term goals include development of new materials for therapeutic nucleic acid delivery, new polymers to deliver chemotherapeutic drugs to hypovascular tumors, and theranostic “turn on” probes that respond to the tumor microenvironment. They aim to globally understand how the physical and chemical properties of materials affect interactions with biological systems in vitro and in vivo in the context of improving cancer therapies. Their research is grounded in chemical design and takes advantage of the unique opportunities for collaborative research at UT Southwestern Medical Center. They ultimately aspire to utilize chemistry and engineering to make a beneficial impact on human health.
The Smith laboratory focuses on the synthesis of complex, bioactive molecules, as well as the development of enabling tools in asymmetric catalysis. Natural products often serve as inspiration for the selection of such targets, and by providing flexible access to these compounds we plan to fine-tune their properties against various diseases and probe their mechanisms of action, with a long-term goal of developing new cancer treatments. In tandem with these efforts, we aim to discover novel catalyst platforms capable of expediting asymmetric access to these targets and chiral small molecules of medicinal value.
Our group is interested in three general areas of research. We develop new catalytic reactions (with an interest in enantioselective molecular rearrangements). We synthesize biologically active natural products (especially polycyclic alkaloids). We also integrate our work in these two areas into medicinal chemistry collaborations for the discovery of novel therapeutic agents
The Tu Lab investigates how metabolism coordinates with fundamental cellular processes such as cell growth, cell division, autophagy, and mitochondria biogenesis. We use budding yeast as a model system and explore related regulatory mechanisms in mammalian cells.
The Williams Lab optimizes small-molecule leads as in vivo tool compounds and therapeutics. We evaluate drug metabolism, solubility, protein binding, and pharmacokinetics. We work closely with chemists to alter these characteristics for optimal activity in vivo. Our primary analytical tool is LC-MS/MS.
The Yu Lab develops novel mass spectrometry technologies (instrumentational and computational) and uses them to address fundamental questions in cancer biology. The processes that transform a normal cell into a cancerous one are often manifested at the protein level. We employ cutting-edge proteomics tools to characterize the cancer-signal transduction networks and to elucidate the molecular mechanisms of tumorigenesis.