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The Strategic Planning Task Force for Translational Science of the UCI School of Medicine, in Collaboration with the UCI Institute for Clinical and Translational Science is pleased to announce the 2013 Collaborative Discovery Grant Awardees

Together with the School of Medicine this grant mechanism funds innovative, and currently unfunded, translational science projects that feature a collaboration of at least two investigators who are project Co-PIs. For this call only projects were focused on infectious diseases.  

Hye-Won Shin & Don Blake: Non-Invasive Diagnosis of Invasive Pulmonary Aspergillosis Using Exhaled Breath Gases »

Hye-won Shin, PhD, Department of Pediatrics
Don Blake, PhD, Department of Chemistry
Non-Invasive Diagnosis of Invasive Pulmonary Aspergillosis Using Exhaled Breath Gases

Project Description
Invasive pulmonary aspergillosis, the most serious fungal infection is by the ubiquitous soil-dwelling fungus, Aspergillus spp., is a major cause of morbidity and mortality in immune compromised pediatric patients. Early and accurate diagnosis is a key to patient outcome. However, current diagnostic tools are often inadequate, insensitive, and fail to determine early Aspergillus infection. The overall goal of this proposal is to identify unique volatile gases in the exhaled breath of Aspergillus-infected pediatric patients. This will then pave the way for using identified breath biomarkers as a novel, non-invasive diagnostic test for invasive pulmonary aspergillosis. The stated goal of this multi-disciplinary project matches the scope of the 2013 Translational Collaborative Discovery Grant and ultimately, resonate with the objectives of the new NIH National Center for Advancing Translational Sciences (NCATS), explicitly, "...to catalyze the generation of innovative methods and technologies that will enhance the development, testing and implementation of diagnostics and therapeutics across a wide range of human diseases and conditions...". Our research team has pioneered efforts to use gas biomarkers in exhaled human breath as markers of disease ranging from asthma and diabetes to cystic fibrosis. In addition, our technical capacity can detect gases emitted from primary and transformed human immune cells in culture and in the headspace above bacterial culture. These experiences allow us to direct the efforts to the problem of rapid and early diagnosis of Aspergillus infection, a disease difficult-to-diagnose and emerging infection importance. In this proposal, experiments are designed to identify gas biomarkers associated with Aspergillus infection by analyzing breath samples from pediatric patients with invasive pulmonary aspergillosis. Experimental controls include breath samples from age-matched healthy children without any infection; and patients with other respiratory infection such as community acquired pneumonia (S. aureus and/or S. pneumoniae). To enhance sensitivity and specificity, a list of gases of interest will be generated from in vitro Aspergillus culture. This list will be used as a reference to determine key exhaled breath biomarkers from patients with invasive pulmonary aspergillosis when compared to the other experimental controls. Each sample will be subjected to a multi column-multi detector gas chromatography apparatus. The analytical system, originally developed to quantify trace atmospheric gases, is capable of measuring breath gases produced by microorganisms in the range of ppb and ppt. This proposal continues an existing robust collaboration among biomedical engineers (Shin) and chemists (Blake) and includes a new but critical addition of clinical infectious disease specialists (Arrieta). 
Weian Zhao & Ellena Peterson: Detection of single bacteria in blood infection in minutes »

Weian Zhao, PhD; Department of Pharmaceutical Science
Ellena Peterson, PhD; Department of Pathology
Detection of single bacteria in blood infection in minutes
 

Project Description
Blood infection caused by bacteria is a major health problem which annually affects over 18 million people worldwide and 700,000 in the U.S. just from sepsis alone, with a mortality rate of approximately 30-40%. A major challenge in blood infection treatment is diagnosis: by the time doctors identify the bacteria species to refine treatment, it can be too late. Indeed, the current gold standard for bacteria detection, blood culture, takes days to get a result while other molecular diagnosis methods such as PCR are often not sensitive enough to detect bacteria that occur at low concentrations in blood (1-100 CFU/mL). We propose a device that rapidly and inexpensively counts bacteria in patient’s blood at singlecell sensitivity without any sample preparation within several minutes. The device integrates a droplet-based microfluidics system with functional DNAzyme sensors that are identified via in vitro selection to specifically report target bacteria with a rapid, real-time fluorescence signal. The confinement of bacteria samples along with DNAzyme sensors into millions of picoliter droplets significantly increases the concentration of released target molecules, facilitating high throughput detection of single bacterial cells in complex mixtures such as blood. In Aim 1, we will integrate DNAzyme sensors that detect E. coli with droplet microfluidics to test and optimize the single-cell detection of bacteria in both buffer and blood. In Aim 2, we will validate the reliability of our device, including both sensitivity and specificity, in clinical specimens by correlating the results of our device with blood culture and PCR. This study will lead to a new paradigm approach for rapid detection of bacteria in blood infections, providing clinicians with needed information to improve treatments and reduce the mortality associated with bacterial blood infections.

Lan Huang & Luis de la Meza: Defining the Structure of Native C.trachomatis MOMP for Vaccine Development  »

Lan Huang, PhD; Department of Physiology and Biophysics
Luis de la Maza, MD; Department Pathology and Laboratory Medicine
Defining the Structure of Native C.trachomatis MOMP for Vaccine Development

Project Description
Chlamydia trachomatis is the main cause of preventable blindness, and the most common sexually transmitted bacterial disease worldwide. Vaccination is the only viable approach to the control and eradication of Chlamydia. The chlamydial major outer membrane protein (MOMP) is the most promising vaccine candidate. Using the native MOMP (nMOMP) as the antigen, significant protection was observed against genital, ocular and respiratory challenges. In contrast, a recombinant preparation of the MOMP (rMOMP), that lacks the correct structural conformation, is a significantly less effective vaccine than the nMOMP. Our assumption is that the rMOMP construct did not present epitopes to the host immune system in the 3-dimensional conformation in which the epitopes appear on intact bacteria. The structural conformation of the nMOMP is unknown. Our goal is to determine the structure of the C trachomatis MOMP using novel cross-linking mass spectrometry technologies for use in the development of a vaccine. These studies will provide much needed structural data to formulate a vaccine to protect against chlamydial infections.  

This is a collaborative project between Drs. Lan Huang and Luis de la Maza. Dr. Huang is one of the leaders in the field of proteomics who has developed and employed novel crosslinking/mass spectrometry strategies to study protein interactions and structures of protein complexes. Dr. de la Maza is the leader in the field of Chlamydia vaccinology and has been studying the native major outer membrane protein (nMOMP) from C. trachomatis for more than 20 years, which is the most promising vaccine candidate. The two PIs form an ideal team to address a major knowledge gap in Chlamydia research by determining the structural conformation of the nMOMP and its protective epitopes for designing a more effective Chlamydia vaccine. The two PIs are among the leaders in their fields and there is no other combination of PIs better qualified to develop a new Chlamydia vaccine. This collaboration will lead to a highly significant scientific and translational breakthrough and benefit the health of tens of millions of people.