The Biumvirate award mechansim is a combined research endeavor with UC Irvine and the Long Beach VA. The selected awardees are science projects that, at its core, have a new device that is used in the promotion of human health, such as in the diagnosis or treatment of human disease. Of greatest interest are projects that have a device that is ready to undergo a new stage of development, e.g., from the lab to first time in humans, from pilot human studies to a formal clinical trial, or from clinical experience to commercial development.
Tuberculosis (TB) remains the second most common cause of death from infection despite the availability of effective antibiotic therapy and a widely used vaccine. Worldwide it is responsible for almost 2 million deaths annually, while the number of multidrug-resistant (MDR) and extensively drug-resistant (XDR) cases is increasing. Over 3,000 people die from tuberculosis each day so it is hard to overstate the need for improved detection and treatment. Even a small reduction in this rate would translate to a significant decrease in human suffering.
One of the main reasons for the great success of Mycobacterium tuberculosis as a human pathogen is its ability to persist for long periods despite host cell-mediated immunity. During this latency there are no obvious symptoms but the bacteria remain alive, and retain the capacity to reactivate and cause clinical disease. An estimated 1/3 of the world’s population has latent tuberculosis, and these individuals constitute a huge reservoir of potential disease. 5-10% of people will develop active tuberculosis in the 2 years following infection, and subsequently the risk of secondary, or reactivation, tuberculosis is approximately 10% per lifetime.
The tuberculin skin test is the mostly widely used method to detect infection with M. tuberculosis. But neither this test, nor the newer -INF assay, can differentiate between active and latent disease. The gold standard for the diagnosis of active disease is the culture and growth of bacteria but this is expensive, difficult and available only in a few centralized hospitals or laboratories. Instead acid-fast bacillus smear microscopy of sputum is generally performed. This test is highly specific in high-incidence settings but only 40-70% of culture positive tuberculosis patients are identified in this manner. In addition in patients with HIV or with extrapulmonary tuberculosis there is a high incidence of smear negative disease. New techniques such as fluorescence microscopy are more sensitive but also more expensive. A limitation for all microscopy and culture techniques is that obtaining a suitable sputum sample is difficult from many patients, particularly young children.
After the outbreak of the XDR TB in Kwazulu-Natal, South Africa the World Health Organization called for an urgent expansion of TB diagnostic services. Clearly there is a need for a new test for tuberculosis that is both sensitive and specific, and can differentiate between active and latent disease.
The long-term goal of this collaboration is to understand the interaction between the immune system and M. tuberculosis that result in either active or latent tuberculosis. The key hypothesis of this project is that by measuring volatile compounds (VC) produced by tuberculosis patients and from M. tuberculosis in vitro, it will be possible to analyze this interaction between the tubercle bacilli and the immune system. At the clinical level we predict this will lead to the development of a new system to detect active tuberculosis, and possibly to differentiate between active and latent disease. At the level of basic science this novel approach should provide insight into the metabolism of the tubercle bacilli during growth and persistence in the human host as well as details of the immune response.
As a first step we will analyze compounds produced by M. tuberculosis during aerobic growth, and in various dormancy models. Our hypothesis is that there will be unique VCs that can be used to differentiate actively growing from nonreplicating M. tuberculosis.
We will measure compounds produced during the course of infection of M. tuberculosis in the human macrophage-like cell line THP-1. Our hypothesis is that there will be unique VCs produced by the interaction of M. tuberculosis and the THP-1 cells that are not produced by either individually.
VCs will be determined in healthy non-infected subjects, patients with active tuberculosis, and those with latent tuberculosis. Our hypothesis is that it will be possible to detect active tuberculosis, and differentiate between active and latent disease by VC production.
Post-traumatic stress disorder (PTSD) patients exhibit significant episodic memory deficits and intrusiverecollections of traumatic events, yet the precise neural underpinnings of these memory abnormalities remainto be determined. Improvements in the characterization of PTSD patients’ memory abnormalities using basiccognitive neuroscience paradigms hold promise as better predictors of individuals at risk for developing PTSD, better predictors of functional outcome, better targets for genome-wide association studies (GWAS), and betterbiomarkers for testing treatment effectiveness. We propose to translate a basic science, pattern separation andcompletion paradigm into clinical research applications in PTSD. Pattern separation is the process offorming non-overlapping representations, while pattern completion is the process of forming a completerepresentations based on partial information. Kheirbek and colleagues (2012) recently proposed that impairedpattern separation, due a deficiency in mature dentate gyrus (DG) neurons, is an endophenotype that underliesthe overgeneralization of fear responses to partial cues observed in PTSD and panic disorder, and that proneurogenictreatments may restore pattern separation and be of therapeutic value. Consistent with thishypothesis, Lissek et al. (2012) found overgeneralization of conditioned fear in panic disorder patients.
The rodent-based model predicts that PTSD patients will show a deficit in DG-dependent pattern separation (required for forming non-overlapping memory representations) and an increase in Cornu Ammonis (CA) 3 /CA1-dependent pattern completion (required for associative retrieval based on partial information). These twoprocesses are critically important for forming and retrieving episodic memories and when disturbed may resultin the episodic memory deficits and overgeneralizations of fear response to partial cues observed in PTSD (aswell as other anxiety disorders). The model can be tested using a memory paradigm sensitive to patternseparation and pattern completion, combined with high-resolution functional magnetic resonance imaging (hrfMRI) of the hippocampus; a combination pioneered by Stark and colleagues. Briefly, Stark et al. performeda continuous incidental encoding task that showed subjects: objects, repeats of the objects, and luresperceptually similar to the objects, while subjects indicate whether the current object shown is “new”, “old”, or“similar”. The task produces a behavioral separation bias metric [p(“similar”[lure]–p(“similar”[foil]: “similar”/”old”response to lure=separation/completion) which assesses an individuals’ pattern separation ability and a brainactivation-based bias score [(first-lure)/(first-repetition)], which expresses similarity between lure activity ascompared with repeat stimulus activity, and assesses a brain region’s involvement in pattern separation (biasscore approaching 0: lure treated as first presentation) or pattern completion (bias score approaching 1: luretreated as a repetition). This study provided the first evidence that DG/CA3 is involved in pattern separation inhumans. The task has been successfully studied in elderly and patients with mild cognitive impairment.
In order to characterize the contributions of hippocampal subfields to episodic memory deficits and severity ofillness observed in PTSD, we propose to test the Kheirbek et al. (2012) PTSD model by investigating patternseparation and completion-associated physiological activations with hr-fMRI in 16 adult PTSD patients and 30age- and sex-matched healthy controls (HC).
We predict that 1a) PTSD patients will show behavioral impairment in object pattern separation, with a shift toward pattern completion (separation bias PTSD < HC); and 1b) PTSD patients will require largerchanges in input (i.e., greater object dissimilarity) in order to recognize that a previously-perceived object isdifferent from a currently-perceived object.
We predict that 2a) consistent with the patternseparation deficit, PTSD patients will show greater similarity between DG/CA3 activations to lure versus repeatstimuli as compared with controls (DG/CA3 brain bias score PTSD > HC); and 2b) consistent with an excess inpattern completion, patients will show CA1/CA3/DG and CA1 activations to lure versus repeat stimuli that aremore similar as compared with controls (CA1/CA3/DG and CA1 brain bias scores PTSD > HC).
We predict that the severity of pattern separation deficit, as reflected by lower separation bias scores is 3a) positively associated with neuropsychological episodic memory deficits; 3b) negatively associated withsymptom severity, in particular the severity of intrusive recollections of traumatic events; and 3c) positively associated with functional capacity and outcome; inverse associations are predicted between brain bias scoresand neuropsychological episodic memory deficits, symptom severity, and functional capacity and outcome.
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For questions regarding funding opportunities, contact Diana Vigil; (949)824-1231.