November 2, 2009 | UW Bioengineering
Ten Bioengineering core faculty members have received more than $3 million in economic stimulus grants.
Recipients are Don Martyn, Daniel Ratner, Xiaohu Gao, Valerie Daggett, Joan Sanders, James Bryers, Patrick Stayton, Paul Yager, Mei Speer, and Larry Crum.
Adjunct faculty with challenge grant awards include Eric Seibel, Mechanical Engineering; Deborah Nickerson, Genome Sciences; David Marcinek, Radiology; Nathan Sniadecki, Mechanical Engineering; David Baker, Biochemistry; Stephen R. Dager, Radiology; and Thomas A. Reh, Biological Structure.
The awards, intended to help grow the nation’s economy, are part of the American Recovery and Reinvestment Act (ARRA) President Barack Obama signed into legislation on Feb. 17. The Obama Administration is focusing on science and technology to drive the economy and anticipated that half of the money would go to universities. The awards were made between May and October, 2009.
The UW, which receives almost $760 million in annual federal research funding (second only to Johns Hopkins University), was well positioned to receive grants from the $10 billion the National Institutes of Health distributed. University administrators predicted a 15 percent increase in federal research funding as a result of the stimulus package. Most new jobs will be technical positions for students, post-doctoral researchers, and technicians.
Below are technical summaries of the grant abstracts from awards to faculty in Bioengineering.
Reducing bacterial infection of implanted medical devices — and reducing the more than $4.5 billion in infection-related medical costs — requires better understanding and control of how bacteria adhere to and colonize a medical implant or device. Bryers' work will quantify the first step — specific adhesion — in the cascading process known as biofilm formation. This small two-year grant, written in collaboration with Wendy E. Thomas, an assistant professor, and Jackie Callahan, a BioE PhD student, will quantify the kinetics of bacteria binding by way of cell surface receptors to select proteins adsorbed on the medical device surface, as a function of fluid shear stresses. Bryers plans to develop a general protocol that defines cellular-level bacterial tissue-device binding. Eventually this work could lead to biomaterial surfaces that prevent biofilm adhesion and diminish the more than two million cases of implant-related infections found each year in the United States.
Daggett, who possesses the world’s largest database of protein folding and unfolding simulations, will use realistic molecular dynamics (MD) simulations in solution to uncover the rules guiding molecular-level protein unfolding and folding.
Daggett’s multidimensional database currently contains over 6,000 simulations of more than 1,000 proteins. The current set represents over 90 percent of all known protein structures with the eventual goal of investigating all proteins folds. Understanding the folding and unfolding process is expected to lead to disease treatments. During folding a protein changes from a disordered and highly dynamic state to a well-ordered and biologically active form. Such folding is critical for protein function. Many neurodegenerative diseases are caused by partial unfolding and the subsequent accumulation of incorrectly folded proteins. Daggett will first seek to determine the general rules of protein unfolding and then investigate three highly populated folds to determine sequence-specific effects.
Gao’s work will focus on a key challenge to effectively applying siRNA technology to targeted cells — developing a new generation of nanocarriers to deliver cancer-targeted siRNA. He will examine the chemical and structural properties of nanoparticles and their effects on siRNA delivery using fluorescent quantum dots. The insight into siRNA behavior he expects to glean from his work could aid in creating siRNA carriers for specific cancer treatment. The project builds on his recent discovery of nanoparticle-amphipol complexes. siRNA can interfere with the expression of a specific gene and be useful in cancer treatment.
Contraction and force of blood flow leaving the heart is determined by the relationship among physical activity, stretching of the heart chambers, and lengthening of their cells, known as the Frank-Starling Relationship. It is also altered by activation of various metabolic pathways that add or subtract phosphates from certain proteins, including thin filament regulatory subunits, myosin regulatory light chains, myosin-binding protein-C and titin. Martyn will determine the effects of varying protein phosphate levels on the level of force generated by the heart during contraction. A detailed knowledge of the components of the Frank-Starling mechanism will be important for designing therapies and interventions to compensate for depressed cardiac function in disease states.
Ratner’s goal is to develop a new generation of ultrasensitive biosensors based on the combination of novel integrated silicon nanophotonic devices and optimized surface chemistries for the presentation of biomolecular ligands using synthetic carbohydrates as model. Real-time label-free glycan biosensors would be invaluable to biomedical research in host-pathogen interactions, vaccine design, cancer biology, immunology, and other fields.
Silicon nanophotonic devices may transform molecular detection, advancing the field of high-throughput screening of small-molecules for drug discovery and Distributed Diagnosis for home healthcare. Silicon-based biosensors can be mass-produced with standard silicon fabrication, providing economies of scale for use outside of the traditional hospital or clinic. By integrating optical and electronic complexity (photonic waveguides and transistors) with these biochemical sensors, thousands of different tests could be performed, in real-time, on a single sample, with a chip that could cost a fraction of the cost of traditional biosensors in large volumes. Such a chip would have enormous impact in areas as disparate as disease diagnosis, global health, biological and chemical warfare, homeland security, home health care and diagnosis, and environmental monitoring.
Joan E. Sanders
The project goal is to create an original and very useful clinical instrument for diagnosis and treatment of residual limb volume fluctuation in individuals who use prosthetic limbs. The lab will enhance its current bio-impedance analysis system to measure in-socket residual limb volume change, conduct measurements on prosthesis-users, and determine if the data accurately characterizes an amputee's diurnal volume fluctuation. The intent is to create an effective tool for providing a quick and quantitative indication of a patient's diurnal limb volume fluctuation status. Potentially this instrument could be extended to other areas of rehabilitation where interstitial fluid control is clinically relevant.
Yanfeng (Mei) Speer
A new scientific researcher will be hired to assist in existing mechanistic studies of vascular cell differentiation and phenotypic modulation within vascular medial calcification, a complication commonly observed in end-stage renal disease and diabetic patients. Technical assistance supported by the award will accelerate the opportunity for the principal investigator to become an independent investigator.
Stayton’s research will focus on developing new drug delivery systems for biomolecular drugs that can target intracellular sites. He will optimize the carriers (pHresponsive carriers for anti-neoplastic siRNA drugs), and then work toward optimizing the pharmaceutical and therapeutic properties of carrier-siRNA. Optimizing the carriers depends on advancing polymer chemistry to design new carriers for siRNA nucleic acid drugs that exhibit reversible membrane destabilizing activity when exposed to endosomal pH gradients.
Multiplexed diagnostic assays that are rapid, easy to use, and very low cost are needed in low-resource clinical settings. Microfluidic systems can bring laboratory-quality multiplexed assays to clinical applications, but so far they require expensive bench-top readers. Lateral flow assays are low cost and easy to use, but generally measure only one substance per device, and are not capable of multi-step chemical processing for sophisticated amplification and sample pretreatment steps. The result is lower test sensitivity and reproducibility. By combining the sophistication of the microfluidic circuit with the simplicity of the conventional lateral flow assay, a team led by Yager and Barry Lutz plans to show that a new diagnostic platform — two-dimensional paper networks — can be used without an instrument to perform complex sets of chemical processes and at a cost-per-test comparable to conventional lateral flow tests. The platform will detect multiple targets from two drops of blood, have a time-to-result less than 10 minutes, be capable of on-board sample preparation, store reagents dry, be usable by an untrained person, and improve sensitivity compared to conventional lateral flow assays — all in a tool the size of a credit card weighing less than 100 gm.
Larry Crum: Challenge Grant
The goal is to improve shock wave lithotripsy and other medical devices to minimize complications in treatment of kidney stones. By improving targeting, and providing real-time feedback to the urologist, it is likely that lithotripters can realize greatly improved patient outcomes. The goal of this proposal is to provide immediate feedback to the urologist during lithotripsy treatment that will improve stone break-up and reduce kidney damage. Kidney stones afflict 13 percent of men and 7 percent of women in the United States and these numbers are rising. Utilizing a novel technique, called "twinkling", Crum’s team has determined that stones as small as 1 mm in diameter can be detected. By detecting stones before they become symptomatic, significant morbidity can be avoided.
Larry Crum: Supplement to R01
Crum will use the imaging and therapeutic capabilities of High Intensity Focused Ultrasound (HIFU) to develop a device and methodology for the intra-operative treatment of profuse bleeding, one of the principal causes of trauma mortality among military combat personnel and others under age 45. His previous findings show that an image-guided HIFU device could induce homeostasis at the site of the wound or occlude the vessels supplying the bleeding site immediately and within the confines of the operating room. Such a device could eliminate the need for significant surgical procedures.
Deborah Nickerson: Next Generation Mendelian Genetics
The goal of Nickerson’s research is to develop a new approach for capturing and sequencing the protein coding regions of the human to identify the candidate genes and mutations that underlie rare Mendelian diseases.
Deborah Nickerson: Northwest Genomics Center
Nickerson is establishing the Northwest Genomics Center that will use next generation sequencing approaches to explore protein coding region variations across 4,000 genomic DNA samples derived from well-phenotyped NHLBI cohorts. The goal is to explore early onset heart, lung, and blood diseases.
Marcinek will create a center for collaborative studies using transformational in vivo diagnostic tools to reveal the roles of mitochondria and cell energetics in cell health and disease using mouse and human muscle model systems.
Sniadecki’s project will examine the role that nanoscale biomechanics play in the formation of blood clots that cause heart disease and stroke.
This project is directed at better understanding the fundamental contributions to the free energy of protein-protein interactions, to redesign protein-protein interaction specificity, and to predict the structures of protein-protein complexes from the structures of the unbound partners.
Dager will add 3-D Proton Echo Planar Spectroscopic Imaging (3D PEPSI) to his longitudinal MRI study of infants at risk for autism to allow measurements of brain chemistry in six-month-old siblings of children diagnosed with autism (high risk) and age-matched infants without a family history of autism (low risk). A secondary goal will be to implement this brain chemical imaging technology at other sites involved in our imaging consortium: University of North Carolina - Chapel Hill, University of Pennsylvania, Washington University (St. Louis), and Montreal Neurological Institute (DCC).
Reh will explore the capacity of central nervous system regeneration following traumatic damage or degenerative diseases using the retina as a model.
A new scanning fiber endoscope will be developed for integrated laser imaging, early tumor identification, staging, and treatment of bladder cancer, using topically applied photosensitizer dyes.
A new image-guided biopsy technology is proposed to improve imaging of bile ducts for cancer diagnosis using a small microscanner for better visibility.