Our laboratory studies an amazing regulatory factor known as NF-kappaB. This transcription factor controls key developmental and immunological functions and its dysregulation lies at the heart of virtually all major human diseases.
Cross-talk between insulin like growth factor -1 and cell adhesion receptors in the regulation of cardiovascular diseases and complications associated with diabetes
Our lab is interested in molecular mechanisms of oncogenesis, specifically as regulated by Ras and Rho family small GTPases. We are particularly interested in understanding how membrane targeting sequences of these proteins mediate both their subcellular localization and their interactions with regulators and effectors. Both Ras and Rho proteins are targeted to membranes by characteristic combinations of basic residues and lipids that may include the fatty acid palmitate as well as farnesyl and geranylgeranyl isoprenoids. The latter are targets for anticancer drugs; we are also investigating their unexpectedly complex mechanism of action. Finally, we are also studying how these small GTPases mediate cellular responses to ionizing radiation - how do cells choose whether to arrest, die or proliferate?
The Cyr laboratory studies cellular mechanisms for cystic fibrosis and prion disease. We seek to determine how protein misfolding leads to the lung pathology associated with Cystic Fibrosis and the neurodegeneration associated with prion disease.
The Dokholyan group focuses primarily on understanding protein dynamics, more specifically on how induced changes in protein folding and aggregation lead to diseases, such as cystic fibrosis, many types of cancers, and a number of neurodegenerative diseases. The Dokholyan group focuses on several such diseases, including Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, and Huntington disease. The Dokholyan group is developing a hierarchy of molecular models, from simplified coarse-grained models to more detailed ones, to create a novel multi-scale simulation methodology. This methodology will enable simulations of large molecular complexes at the biologically-relevant time scales, thereby allowing to directly glance into processes associated with human diseases. Member of the Molecular & Cellular Biophysics Training Program.
The research in my lab is divided into two main areas - 1) Atomic force microscopy and fluorescence studies of protein-protein and protein-nucleic acid interactions, and 2) Mechanistic studies of transcription elongation. My research spans the biochemical, biophysical, and analytical regimes.
Genetic instability in cultured human cells and yeast, microsatellite mutations, DNA mismatch repair, hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome), human genetics, somatic-cell genetics.
We study intracellular trafficking of the chloride channel CFTR in heterologous systems and in primary human airway epithelial cultures. The most common mutation in cystic fibrosis, deltaF508, results in a misassembled protein that is retained at the ER but can escape and proceed to the plasma membrane by addition of small molecule correctors or low temperature incubation. Temperature-rescued deltaF508 disappears rapidly from the cells surface and is subjected to lysosomal degradation, while wild-type CFTR is recycled back to the plasma membrane. Of particular interest is the mechanism that leads to elimination of detlaF508 from the cell surface.
Dr. Gulley's research is on Epstein-Barr virus (EBV)-related malignancies. Molecular and immunohistochemical techniques are used to characterize infected tissues. We validate new assays to help diagnose and monitor affected patients.
This laboratory focuses on the identification of signaling pathways regulating host/bacteria interaction and the pathological consequences of a dysregulated response. Using germ free mice and gnotobiotic approaches, we investigate the functional impact of toll-like receptor (TLR) and nucleotide oligomerization domain (Nod) signaling on bacteria-mediated intestinal inflammation, colitis-associated colon cancer and intestinal response to injury (ischemia-reperfusion, radiation).
Research interests include: 1) Regulation of signal transduction and cell growth by integrin-mediated cell adhesion and 2) Therapeutic drug design and delivery.
Our lab is focused on the development of HIV-1 vectors for gene therapy of genetic disease. In addition, we are using the vector system to study HIV-1 biology. We are also interested in utilizing the HIV-1 vector system for functional genomics.
Our research focuses on the structure and function of medically important proteins from the crystallographic approach. The current topics include cycolphilin, calcineurin, heat shock protein 90 (hsp90), and cyclic nucleotide phosphodiesterase.
I study a canine model of Duchenne muscular dystrophy. Both conditions occur due to mutations in the dystrophin gene. Our research has defined clinical and pathologic features to better understand disease pathogenesis and to assess treatment.
Our research is focused on the genetics and molecular pathology of complex multi-factorial conditions in humans - obesity, diabetes, hypercholesterolemia, insulin resistance, and hypertension. These conditions underlie cardiovascular diseases, including atherosclerosis, the major cause of death and disabilities in North America. Our approach consists of experiments with mice carrying modifications in various genes important for the maintenance of vascular function, antioxidant defense, and metabolism. We dissect how gene-gene and gene-environment interaction influences the pathogenesis of these common human conditions and their
complications.
The overall goal of our laboratory is to obtain new insights into the host-virus interaction, particularly in HIV infection, and translate discoveries in molecular biology and virology to the clinic to aid in the treatment of HIV infection. A subpopulation of HIV-infected lymphocytes is able to avoid viral or immune cytolysis and return to the resting state. Current work focuses on the molecular mechanisms that control the latent reservoir of HIV infection within resting T cells. We have found that cellular transcription factors widely distributed in lymphocytes can remodel chromatin and maintain quiescence of the HIV genome in resting CD4+ lymphocytes. These studies give insight into the basic molecular mechanisms of eukaryotic gene expression, as well as new therapeutic approaches for HIV infection.
My laboratory studies diffuse gliomas, devastating primary tumors of the central nervous system for which few effective drugs are currently available. We utilize model systems (genetically engineered mice, cultured cells, and human tumor specimens) to explore the molecular pathogenesis of
and develop drugs and diagnostic markers for individualized therapy of gliomas. Rotating students gain experience with techniques that include genomics (expression microarrays and array CGH), fluorescence microscopy, computer-enhanced image analysis, and tissue microarrays.
We are identifying genetic variants that influence common human traits with complex inheritance patterns, and we seek to understand the biological function of the identified variants. Currently we are investigating susceptibility to type 2 diabetes and obesity, as well as variation in cholesterol levels, blood pressure, body size, weight gain and early growth. In addition to examining the primary effects of genes, the lab is exploring the interaction of genes with environmental risk factors in disease pathogenesis. Approaches include genome-wide association studies, genetic epidemiology, resequencing, bioinformatic analysis, molecular biology, cell biology, and mouse models to compare high- and low-risk alleles in a whole-animal setting.
Our lab investigates molecular and cellular mechanisms that regulate mammalian spermatogenesis and fertilization. A major focus of our current research is sperm energy metabolism. Our gene knockout studies demonstrate that glycolysis is essential for sperm motility and male fertility, and genomic analyses indicate that male germ cells express unique enzymes for nearly every step in this central metabolic pathway. These sperm-specific glycolytic enzymes have distinctive properties, as demonstrated by biochemical and structural analyses. Understanding how sperm energy production is regulated has significant therapeutic potential, both for the development of new contraceptive strategies and the clinical management of infertility.
Fertilization leads to the formation of a new diploid individual and represents an exquisite example of the specificity of cell to cell and cell surface-extracellular matrix interaction. Our research laboratory is interested in the study of the structure and function of sperm proteins. The long-term goal of our research is to define a set of sperm molecules that are necessary for one or more steps in the fertilization process. A full understanding of the mechanisms of sperm maturation and fertilization would allow precise targets for both infertility diagnosis and contraception.
Currently, the structure and function of two different proteins are under study. These proteins are: 1) NASP a nuclear protein that binds and transports linker histones into the nucleus and is critical for mitosis and meiosis; 2) Eppin a testis and epididymal serine protease inhibitor.
An important step in the development of tests for the diagnosis of infertility and for the development of a male gamete based contraceptive is the determination of specific protein-protein interactions that are necessary for fertilization. Characterization of these interactions will
provide sites for contraceptive development.
We examine dynamic cellular processes using structural biology. Current projects focus on Infectious disease, particularly the spread of antibiotic resistance and host-pathogen interactions; Protein-DNA complexes involved in DNA manipulation; the Design of protein therapeutics; Nuclear receptors in transcriptional control; and Enzymes central to drug recognition and metabolism.
Bioinformatics, Cancer Biology, Cell Biology, Chemical Biology, Computational Biology, Genomics, Molecular Medicine, Neurobiology, Pharmacology, Systems Biology, Toxicology, Translational Medicine
My laboratory at present is working on the vitamin K cycle and vitamin K-dependent proteins. The enzymes of the vitamin K cycle include, at a minimum two integral membrane proteins, both of which were purified and cloned by my laboratory. One, the vitamin K epoxide reductase is the target of warfarin for which 40 million prescriptions are written each year in the US alone. Polymorphisms in this gene are the best example to date of the use of genomics in molecular medicine. We are also interested in purifying any additional components of this cycle and trying to understand the ~50% of patients whose genotype is not informative about warfarin dose. In addition, we are interested in the mechanism of how factor VIIa works and the role of the extracellular matrix in coagulation.
Dr. Tidwell's research is focused on the design and synthesis of new drugs for the treatment of AIDS-associated opportunistic infections. The rationale for design of new drugs is directed at determining the mechanisms of action, antimicrobial activity, and pharmacokinetics of dicationic molecules. Studies have been initiated to isolate and identify new drug targets from Pneumocystis carinii and Cryptosporidium parvum utilizing molecular modeling and biochemical methods to aid in the determination of new structures. The role of proteases and imidazoline receptors in the pathogenesis of disease continues to be a major area of research as well as a new prodrug approach for the cationic molecules to allow for much improved bioavailability.
The major area of our research is Biomolecular Informatics, which implies understanding relationships between molecular structures (organic or macromolecular) and their properties (activity or function). We are interested in building validated and predictive quantitative models that relate molecular structure and its biological function using statistical and machine learning approaches. We exploit these models to make verifiable predictions about putative function of untested molecules.
My laboratory is interested in characterizing the role of cytoplasmic signal transduction pathways in regulation of androgen receptor activity and progression of prostate cancer. Our studies have focused on HER-2 receptor tyrosine kinase and we have demonstrated that HER-2 activation stimulates androgen receptor activity and HER-2 inhibition inhibits androgen receptor transcriptional function at the level of recruitment to the androgen responsive enhancers. These findings have led to the design and initiation of the protocol involving lapatinib, a clinical HER-2 inhibitor, in treatment of patients with prostate cancer. More recently, we have demonstrated that activated Cdc42-associated kinase Ack1 promotes progression of prostate cancer via tyrosine phosphorylation of androgen receptor at Tyr-267 and Tyr-363
residues. We are interested in further characterizing the role of tyrosine phosphorylation of androgen receptor in prostate cancer and development of Ack1 targeted therapy for clinical use.
Cellular, molecular, and biochemical mechanisms of blood coagulation; Relationships between cells (monocytes, fibroblasts, endothelial cells, smooth muscle cells, platelets and others), plasma protein concentration, thrombin generation and blood clots; Fibrin formation, structure and stability; Mechanical properties of fibrin; Disorders associated with bleeding and thrombosis, including hemophilia and cardiovascular disease (heart attack, stroke, deep vein thrombosis, pulmonary embolism); Preclinical testing of hemostatic and antithrombotic drugs
Our lab is interested in how dynamic changes in chromatin structure affect gene expression, cell lineage determination and cancer development. Currently, we are focusing on two epigenetic modifications, DNA methylation and histone methylation.
