Genetic variation, internal states, and environmental cues converge on shared neuronal circuits to regulate behaviors. In the nematode worm Caenorhabditis elegans, an anatomical wiring diagram provides an essential map for innate behaviors, such as preferences for specific stimuli. Superimposed on this detailed circuit diagram are neuromodulators reflecting internal states, which help select appropriate behavioral responses from a larger number of latent circuits, and lead to both rapid and long-lasting changes in behavior. Dr.
Recently, genetic experiments in mice identified the heparan sulfate proteoglycan syndecan-1 as an important receptor for the clearance of triglyceride-rich lipoprotein (TRL) in the liver. This binding site for the TRLs consists of a protein core and one or more heparan sulfate chains. Binding depends on the heparan sulfate chains based on the accumulation of plasma TRLs in mice bearing mutations in heparan sulfate biosynthesis. To identify the major apolipoproteins that mediate binding to the heparan sulfate chains, we developed a series of in vitro and in vivo assays.
Epidemiology was born of the need to discover the evidence necessary for the practice of public health. Early generations of epidemiologists produced data with the objective of translating their findings into public health action. However, the need for epidemiology to establish its scientific credentials, and the fact that subsequent generations of epidemiologists lacked a public health background, eventually resulted in an almost exclusive focus on etiology.
The Wu laboratory investigates the biochemical basis for histone H2A.Z exchange using the budding yeast model organism. They have identified the yeast SWR1 ATP-dependent chromatin remodeling complex as the responsible enzyme. In a purified system, SWR1 removes H2A-H2B dimers from nucleosomes and deposits free H2A.Z-H2B dimers in an ATP-dependent manner. Homologous enzymes have since been characterized in mammalian systems. How does SWR1 recognize promoters and enhancers genome-wide?
Dr. Saphire’s lab studies viruses with compact genomes that encode just four to seven genes each. Viruses with limited genomes offer a defined landscape of possible protein-protein interactions. Each protein is critical—many are obligated to perform multiple functions and some rearrange their structures to achieve those new functions. As a result, these few polypeptides accomplish a surprisingly complex set of biological functions including immune evasion, receptor recognition, cell entry, transcription, translation, assembly and exit. Dr.
Prior to joining TGen, Dr. Carpten was an intramural tenure track investigator with the Cancer Genetics Branch of the National Human Genome Research Institute (NHGRI), NIH, a group that pioneered a number of innovative technologies and methods to study the underlying genetics of cancer. At NIH, he co-led the first published genome wide scan for prostate cancer susceptibility genes published in 1996 in Science. His lab subsequently discovered germ-line mutations in theRNASEL gene in HPC1-linked hereditary prostate cancer families.
Dr. Linehan has had a long-standing interest in identification of the genetic basis of cancer of the kidney. Kidney cancer is not a single disease. It is made up of a number of different types of cancer, each of which has a different histology, a different clinical course, which respond differently to therapy and are caused by different genes. Studies of the kidney cancer gene pathways have revealed that kidney cancer is fundamentally a metabolic disease.
For 50 years the world believed that mutations occur at random. The discovery of stress-induced mutagenesis has changed ideas about mutation and evolution and revealed mutagenic programs that differ from standard spontaneous mutagenesis in rapidly proliferating cells. The stress-induced mutations occur during growth-limiting stress, and can include adaptive mutations that allow growth in the otherwise growth-limiting environment.
GATA binding factor 2 (GATA2) was initially cloned in 1991 as a critical regulator of murine endothelial development, the complete absence of which was incompatible with life. Subsequent work confirmed that it was also critical for hematopoiesis, erythropoiesis, and macrophage function. After almost 20 years of characterization of patients with disseminated mycobacterial infections who had monocytopenia, B cell and NK (natural killer) cell cytopenia, Steve Holland’s group found heterozygous mutations in the same transcription factor, GATA2, accounting for their disease.
The Patient Centered Outcomes Research Institute (PCORI) was authorized by Congress — in legislation that was coincident with the Affordable Care Act — to conduct research to provide information about the best available evidence to help patients and their health-care providers make more informed decisions. Since 2010, a research infrastructure has been created to support a different model of clinical research. Practical questions impacting health-care delivery, unmet clinical needs, and health-care inequities are being explored through extensive measures of patient engagement.
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