Rosen Center Pilot Grant Awards
Rosen Bioengineering Center Pilot Research Grants provide $80,000 to support collaborative early-stage projects that require sharing of ideas, people and resources between labs. The goal of the program is to help teams develop strong preliminary data that will enhance their competitiveness for large, collaborative awards from external agencies like NIH, NSF, DoD and others.
Title: Engineered viruses for large-scale targeted genetic manipulation in mice
Awardees: Carlos Lois and Viviana Gradinaru
The Lois and Gradinaru team plans to develop and optimize new experimental strategies using engineered viruses to allow investigators to investigate the role of genes in physiological processes at a much larger scale than possible with conventional technologies. The ability to genetically manipulate genes in whole animals has revolutionized biological investigation. In particular, the use of genetically engineered mice has become an extremely useful tool to study the role of genes in development and disease in an animal model that is a very useful comparison with human physiology and pathology. However, an important bottleneck for experiments involving use of genetically engineered mice is related to the long time necessary to generate these animals, and to breed them to achieve homozygosity. In addition, genotyping and maintaining animals is labor intensive and costly. This bottleneck severely restricts the number of genes that can be studied. For example, in many situations there are several dozen candidate genes thought to be involved in a given process. However, it is not practical to study all of these candidates as the amount of time, effort, and cost would be prohibitive. Recent developments in transgenic technology (mainly CRISPR/cas9) have provided new methods that allow investigators to genetically modify cells in a much more efficient manner than with previous techniques. However, even with this higher efficiency, producing mutant mice still costs approximately 3,000 dollars per transgenic line, without including any of the subsequent costs related to maintenance of the transgenic lines.
Title: Constraining the mechanisms of extracellular electron transfer (EET) in Pseudomonas aeruginosa biofilms by studying the effects of eDNA-binding on phenazine reactivity
Awardees: Dianne Newman and Jacqueline Barton
The Newman and Barton team will focus on phenazine molecules produced by the model biofilm-forming bacterium, Pseudomonas aeruginosa PA14. Biofilms are multicellular aggregates, often associated with a surface. Within biofilms, steep nutrient gradients form because cellular consumption rates outpace that of diffusion. We are interested in how cells that are oxygen-limited in the centers of biofilms sustain metabolic activity compared to cells on surfaces of biofilms that have direct access to oxygen. Extracellular DNA (eDNA) constitutes a large fraction of the biofilm matrix. With support from the Rosen Center, we seek to constrain how small organic molecules excreted and recycled by biofilm cells (“extracellular electron shuttles”) interact with eDNA. We will test the hypothesis that eDNA provides a framework into which phenazines intercalate, facilitating their retention and ability to conduct electrons within biofilms. Our in vitro studies will lay a strong foundation for future experiments to determine the mechanism of EET through the biofilm matrix. Ultimately, lessons learned by studying EET in simple single- and multi-species biofilms will inform the design of synthetic biofilm systems for use in diverse applications.
Title: A Miniature, wireless and implantable intraocular pressure sensor
Awardees: Yu-Chong Tai and Azita Emami
The Tai and Emami team is working together to develop a miniature, wireless, and implantable pressure sensor device that can maintain its sensor accuracy for long-term application (e.g., >24 months) in the body. This advanced sensor packaging is based on the previous Caltech success of a preliminary proof-of-concept pressure sensor. Our new approach of this packaging method is designed to tolerate biofouling while still maintaining pressure sensing accuracy. In this collaborative effort, Emami's lab will develop the wireless electronic chip that interfaces with the sensor chip. The electronic chip powers up the sensor via RF power harvesting, programs the sensor and enables wireless data communication to/from the implant. Tai’s lab will be responsible for the pressure sensor but both labs will integrate the sensor together. Initially, the team will collaborate with the Department of Ophthalmology at USC to target for Glaucoma applications. We plan to demonstrate a new wireless pressure sensor that can monitor, record and provide warning of abnormal intraocular pressures 24/7. The long term goal is to expand the use of the sensors for other continuous internal body fluid pressure monitoring in the heart, brain bladder and other organs, rather than snapshot measurements taken in the clinic.
Title: 3-Dimensional Nano-Architectures for In-Vivo Biomedical Measurements
Awardees: Julia Greer and Joel Burdick
The Greer and Burdick groups will develop a novel sensing technology platform, based on 3-dimensional (3D) nanolattices, for in-vivo and minimally invasive sensing of stress in biological tissues and cavities. The Greer group has demonstrated that lightweight, high strength/stiffness, nano-architected materials can act as sensors through strain-modulated optical response. When properly engineered, these devices offer the potential for non-invasive interrogation of biological stresses and pressures via the optical response of the implanted sensors. Spinal cord injury (SCI) research and therapy, where there is a critical need to non-invasively monitor intra-spinal pressure post-injury, is a motivating application, but the proposed technology has broader applications because of its potential to be minimally invasive and because of its microscale deployment. Piezoelectric materials, like quartz and ZnO, can alternatively be integrated with nanolattice components to enable conversion of nanolattice strain into an electric charge, which in turn can be transduced into a sensory signal. This effort will analyze, design, optimize, and demonstrate nano-architected sensors with photonic and electronic responses for in-vivo and minimally invasive biomedical sensing.
Title: Visualizing nicotine entry into midbrain dopaminergic neurons
Awardees: Henry Lester and Changhuei Yang
The Lester and Yang team aims to employ a new computational imaging method, EmSight, to study the impact of nicotine on DA neurons over month-long experiments to examine possible cell-delimited mechanisms of chronic nicotine. Dopaminergic (DA) neurons play a role in several neural disorders, including schizophrenia and Parkinson's disease. Chronic exposure to nicotine changes the physiology of DA neurons in ways that are not well understood but that have shown evidence of neuroprotection.
Title: Dynamic single-cell imaging of long-range physical interactions among regulatory DNA elements and target genes
Awardees: Ellen Rothenberg and Barbara Wold
The Rothenberg and Wold team is collaborating on a novel technology that will provide better understanding of long-range DNA interactions that regulate transcription and are responsible for determining cellular identity. The development of healthy cells requires proper control at the level of transcription. Improper control often results in the development of disease. For example, a severe kind of acute lymphoblastic leukemia (ALL) can arise when precursor T-cells carry out the wrong transcriptional messages during their development and fail to change their transcriptional activity in a properly coordinated way. And altered transcriptional regulation is central in the genesis of childhood tumors of muscle and bone. There has been great progress using static snapshots to identify molecules that play roles in transcriptional control, but the dynamics of how these molecules work together in live cells have been obscure. The technology generated by the Rothenberg and Wold team will now make visible, for the first time, the living dynamics of long-range physical DNA interactions important for regulating changes in transcriptional activity within individual cells. This technology, and the knowledge gained from its use, is expected to enable vital breakthroughs in understanding the roles of control systems that guide precursors to healthy differentiated cell identities.
Past Rosen Research Project Awards
Frances Arnold and Richard Murray “Systems Engineering of Microbial Stress Response”
John O. Dabiri for graphic design services to develop visual elements for an advanced biomechanics textbook
Chin Lin Guo “Engineering Self-assembled Tubular Systems”
Richard Murray “Forced Response Analysis of Biomolecular Circuits”
Richard Murray, iGEM Team funding to allow a group of Caltech undergraduate students to compete in the International Genetically Engineered Machine competition
Rob Phiillips “Teaching at the Interface: A Vision for Quantitative Biology”
Erik Winfree hosted the 17th International Conference on DNA Computing and Molecular Programming (DNA17) at Caltech