Princeton University

Professor David Botstein has received a $706,000 award from the National Institutes of Health to support the acquisition of an ultra-high throughput-sequencing instrument with a wide range of cutting-edge applications, including dynamic studies of gene expression, DNA binding and nucleosome positioning as well as new ways to assess gene function genome-wide. The new machine will support ongoing research efforts and enable new initiatives in Princeton's National Institute of General Medical Sciences-funded Center for Quantitative Biology.

Professor Rebecca Burdine was granted $64,000 from the National Institutes of Health to continue her work using zebrafish to study left-right patterning, a biological mechanism that enables the proper positioning of organs in the body cavity during development. In particular, Burdine and her collaborators focus on cloning and characterizing zebrafish mutations that result in left-right patterning defects. As similar problems are known to cause heart defects in around 1 in 5,000 human infants, the work may contribute to a heightened understanding of the genetic basis of congenital heart disease.

Professor Jonathan Cohen has received $204,000 from the National Institutes of Health to support his work on the role of the brain systems that regulate decision-making. The new funds will enable Cohen and his collaborators to obtain new experimental data using a recently acquired machine that enables the use of functional magnetic resonance imaging (fMRI) and electroencephalographic (EEG) methods simultaneously to obtain data on neural mechanisms. This offers a significant advantage over performing fMRI and EEG experiments on the same subjects in parallel, as the experiments are highly sensitive and may not be replicable. The ultimate goal of the research is to enhance the understanding of the role decision-making brain systems play in cognitive and behavioral disturbances.

Assistant professor Hilary Coller has received a $250,000 subaward from a National Institutes of Health grant to Rutgers University to investigate how tumor cells and normal cells employ autophagy, or cellular self-consumption, in response to metabolic stress, such as oxygen or nutrient deprivation. Stressful conditions are common in tumor environments, and autophagy provides cells with a high level of tolerance by maintaining energy balance and eliminating malfunctioning cellular parts. The research will heighten understanding of tumor cell metabolism and help define how differences in metabolism and stress response alter the interaction between normal and tumor cells, providing new insights that may one day inform cancer therapy.

Professor Edward Cox was granted $254,000 from the National Institutes of Health to continue his research on the Ras superfamily of genes, which are involved in cell signaling and intracellular protein trafficking. Genes in this family are activated or mutated in around half of all human cancer cases, and an understanding of this process is a major goal for cancer research and therapy. Cox's research supports a crucial step toward success in this endeavor -- the development of new techniques that rapidly and accurately detect certain chemical changes that take place when Ras gene activation occurs.

Professor Jonathan Eggenschwiler has received $66,000 from the National Institutes of Health to further his study of a pathway known as the hedgehog signaling pathway, which plays a key role in many aspects of mammalian development, including cell fate determination, pattern formation and differentiation. Eggenschwiler and his collaborators focus on mechanisms that control the pathway, with implications for the development of ways to diagnose, prevent and treat birth defects and cancers that result from its faulty regulation.

Professors Lynn Enquist and Samuel Wang were awarded a $993,000 National Institutes of Health Challenge Grant to develop and test a new method for the study of brain connectivity. Viral tracing methods, which use specially constructed viruses to trace neural circuits, have become an essential tool in neuroscience research. The biologists will construct a new type of viral tracer that will not only mark a connected neural circuit, but report on the circuit’s activity, offering a distinct advantage over existing tracers. These new capabilities may offer insights into neural circuit organization that were previously impossible to achieve.

Wang also was awarded $500,000 from the National Institutes of Health to support ongoing fluorescence microscopy work that has implications for understanding a variety of human health problems, including birth defects, viral infection, neurological disease and cancer. The grant will enable researchers to perform microscopy with enhanced depth of focus and greater duration of observation, allowing them to track rapidly moving intracellular particles, morphological change and biochemical dynamics on a subcellular scale with movie-quality time resolution.

Professor Elizabeth Gavis has received $458,000 from the National Institutes of Health to support her ongoing work on the localization of messenger RNA (mRNA)—a type of molecule that codes for protein synthesis. mRNA localization is a mechanism used by many cells to ensure the restricted accumulation of certain proteins in appropriate areas of the cell, which is essential for normal embryonic development. Previous studies of mRNA localization have focused on a relatively small number of mRNAs in select cell types; Gavis and her colleagues will use a novel genome-wide screen to test whether numerous mRNAs are localized in many different cell types in Drosophila. As altered regulation of mRNA localization has been associated with many types of cancer as well as neural defects, the work may enhance the understanding not only of how localized mRNAs control cellular processes needed for development, growth and development, but how the disruption of these processes may lead to disease.

Professor Elizabeth Gould has received $109,000 from the National Institutes of Health to explore the effects of rewarding experiences on age-related cognitive decline in rats. Evidence suggests that positive life experiences may stimulate the growth of new neurons in the adult hippocampus -- a brain structure that plays a key role in learning and memory. Gould and her collaborators will focus on the interrelationships among sexual experience, aging and the structure of the hippocampus with the ultimate goal of understanding the mechanisms that contribute to and resist against learning and memory impairments wrought by the normal aging process.

Assistant Professor Uri Hasson was awarded a $220,000 subaward from a National Institutes of Health grant to New York University to study the neural correlates of effective drug prevention messages. Although drug prevention advertisements have been used for decades and are an important part of anti-drug policy, there is considerable controversy over their effectiveness and a growing need to develop new assessment tools to measure their efficacy. Hasson and his collaborators will combine methods from marketing with functional magnetic resonance imaging (fMRI) and skin response and eye movement data to determine engagement in and effectiveness of anti-drug ads, enabling the detailed characterization of activation patterns associated with engagement.

Professor Fred Hughson has received $118,000 from the National Institutes of Health to continue ongoing research on quorum sensing, a process of cell-cell communication that allows bacteria to collectively control processes including biofilm formation and the secretion of virulence factors. The award will enhance the X-ray diffraction capabilities of Hughson and his collaborators, allowing them to determine the crystal structure of key molecules involved in the quorum sensing process. The research team is especially interested in identifying molecules that target quorum sensing to inhibit virulence in the cholera pathogen.

Professor Laura Landweber has received $808,000 from the National Science Foundation to study mechanisms that bypass traditional modes of genetic inheritance in a single-celled, pond-dwelling organism called Oxytricha. These unusual, "epigenetic" mechanisms rely on strands of RNA to pass physiological modifications acquired throughout life from a parent organism onto its offspring. In humans, this would be akin to a female weightlifter passing her large muscles onto her children, even though her strength was developed through life experience and not coded in her DNA. An investigation of this RNA-guided process will enhance conceptions of adaptation and evolution in microbes, and could also have implications for the understanding of cancer and other diseases associated with the rearrangement of DNA.

Assistant professor Manuel Llinas has received a $174,000 subaward from a National Institutes of Health grant to the Albert Einstein College of Medicine of Yeshiva University to continue work on a recently identified group of DNA binding proteins in certain parasites that are likely to play key roles as regulators of development in these organisms. Llinas and his research group will use high-throughput protein binding microarray technology to develop a comprehensive understanding of all DNA binding interactions for this protein family.

Professor Mark Rose was awarded $100,000 from the National Institutes of Health to continue his work on cell fusion in yeast, which has close parallels to developmental processes in all sexually reproducing organisms. When yeast cells fuse, or conjugate, they exit the normal cell cycle and express proteins that are necessary for fusion. Similarly, in human development, cells must stop dividing for differentiation to occur. Working with some 6,000 yeast mutant strains, Rose will use two state-of-the-art techniques to investigate the effects of premature fusion in yeast cells and identify which genes become toxic to the cell when this occurs. The effort may contribute to a greater understanding of normal developmental processes and problems, such as cancer, that may develop when they go awry.

Professor Jean Schwarzbauer was awarded $85,000 from the National Institutes of Health to support her work on the specific signals from the extracellular matrix—the proteins that surround living cells—that direct organ development and control organ function. The support will provide a new imager and light source to improve the ability to capture high-resolution images of living cells in model organisms, enhancing the sensitivity of the research and the rate of data collection. As human disease progression depends on perturbations in the extracellular matrix, the work will provide new ideas about how these disruptions affect organ development and contribute to disease.

Professor Thomas Shenk was granted $173,000 from the National Institutes of Health to support his ongoing investigation of genes in the human cytomegalovirus (HCMV) that regulate interaction with the host cell and control viral replication and disease development. A widespread pathogen, HCMV is the largest infectious cause of birth defects and also produces disease in immuno-compromised adults. The new funds will allow Shenk and his collaborators to use state-of-the-art genomic technologies in combination with their recent results to accelerate their progress toward elucidating the HCMV infection mechanism and replication strategy.

Professor Thomas Silhavy was awarded $235,000 from the National Institutes of Health to continue his research on the outer membranes of E. coli bacterial cell envelopes. Specifically, Silhavy and his collaborators will probe how E. coli outer membranes form vesicles and control the translocation of proteins across the membrane. Pathogenic bacteria use outer membrane vesicles to secrete disease-causing molecules, and these membranes also often serve to protect the organisms from toxic compounds, including antibiotics. Additionally, Silhavy and his collaborators previously demonstrated that a gene with the potential to contribute to cancer growth in humans can function in the control of protein translocation in E. coli. By increasing the molecular-level understanding of how bacterial membranes work, Silhavy's work may provide insights into both infectious disease and cancer.

Professor Mona Singh has received $200,000 from the National Institutes of Health to continue her work on the development of methods and software to predict protein interactions, as well as the creation of new analytical techniques to derive meaningful information from maps diagramming how thousands of proteins interact in a given cell. A sophisticated knowledge of protein interactions, in conjunction with an in-depth comprehension of cellular regulatory and signaling pathways, is essential to an increased understanding of cells and diseases on the systemic level. Singh’s work will focus specifically on zinc finger proteins, which play an important role in many disease pathways, including cancer.

Professor David Tank has received a $1 million National Institutes of Health Challenge Grant to support the development of virtual reality technologies that will improve the study of neural circuits in awake rodents. These systems will be used in conjunction with laser scanning microscopes and cellular activity recording techniques to monitor neural activity as the animals navigate virtual environments. Together, these technologies will provide breakthrough capabilities for the cellular analysis of circuits in awake, behaving rodents. 

Tank also has received $187,000 from the National Institutes of Health to supplement his work on imaging and stimulating neural activity in awake mice. The award will support the improvement of laser light sources used to observe cellular activity in the brain as mice navigate a virtual environment. By optimizing experimental methods and enabling the imaging of deeper brain structures, the project addresses many longstanding questions in neuroscience, including how to distinguish between active and silent neurons during a specific behavior, and how synchronous neural activity informs perception, memory and motor control.

Associate professor Saeed Tavazoie was awarded $391,000 from the National Institutes of Health to characterize the genetic basis of antibiotic resistance in E. coli bacteria. Rising levels of antibiotic resistance are contributing to the creation of "superbugs" that are immune to traditional pharmaceutical interventions and threaten human health. Tavazoie and his collaborators will use a "genetic footprinting" technique to explore the role each and every gene in the E. coli genome plays in antibiotic resistance. An increased understanding of the genetic pathways and networks behind this phenomenon could provide guidance for the development of new drugs and therapeutic regimes.

Professor Virginia Zakian was awarded $347,000 from the National Institutes of Health to continue her research on the regulation of yeast telomerase, an enzyme that acts on the ends of chromosomes. Her work has vast implications for human health, as human telomerase expression is heightened in most human tumors and associated with their unlimited growth potential. Additionally, there are very low levels of telomerase in human stem cells, and even slight reductions in the amount of enzyme in these cells can have dire effects on life span.