2012 CTRI Pilot Project Awardees

Clinical Awardees

$ 25,000

Awardee: Jason Sicklick, MD
Assistant Professor, Department of Surgery
Innovative Targeting of Melanoma with Allosteric RAF inhibitors

Abstract: Overall objective of this project is to define the role of concurrent BRAFV660E/CRAF/PDGFR allosteric inhibition within the context of melanoma, a disease for which there remains limited therapeutic options.

Aim 1, we will characterize a series of highly potent AKIs using vemurafenib-sensitive and -resistant melanoma lines. We will define allosteric RAF inhibitor effects on cell viability, apoptosis and cell cycle arrest in a time-/dose-dependent fashion.

Aim 2, we will investigate how AKIs influence intracellular kinase signaling pathways and control tumor cell proliferation, apoptosis and necrosis using pharmacologic and genetic analyses.

 

Awardee: Jeannie Huang, MD, MPH
Associate Professor, Department of Pediatrics
Neurobiology of Pain Processing in Children with Gastrointestinal Disorders

Abstract: The current proposal will use blood oxygen level-dependent (BOLD) fMRI to evaluate the neurobiology of the ain response in patients with IBD, in patients with FGID, and in age and sex matched controls. The underlying hypothesis of this work is that the CNS modulates gastrointestinal symptoms and accompanying functional and inflammatory changes via interoceptive gut-CNS system axes. We will build on prior protocols developed by Dr. Walter Kaye and colleagues that evaluate stress responses using fMRI in anorexia patients.

The aims of the current project are as follows:

1. To adapt the UCSD fMRI pain induction protocol and to establish the adjusted paradigm for children with chronic gastrointestinal symptomatology. This aim will utilize a method currently used to evaluate anticipatory and neuronal activation in response to pain stimuli in youth with anorexia, based on an established protocol at UCSD.

2. To investigate how brain activity associated with the anticipation (stress) and processing of pain in children with IBD and FGID differs from brain activity among normal, healthy children. To achieve this aim, we will test the activation of portions of the brain associated with the neurobiological response to stress and pain.

 

 

Awardee: Xavier Soler, MD, PhD
Assistant Professor, Department of Medicine
Effects of Pulmonary Rehabilitation on sleep architecture, obstructive sleep apnea, insomnia and nocturnal hypoxemia in COPD

Abstract: The primary aims of this pilot study are to perform and collect preliminary data to: 1)Characterize OSA, sleep architecture, insomnia and NOD in COPD population. 2)Evaluate changes on OSA severity, insomnia, sleep architecture and NOD after PR. Secondary aim will be: 1)Evaluate the relationships between OSA, insomnia and NOD with health outcomes (i.e., quality of life).

We hypothesize that in patients with moderate to severe COPD: 1) OSA is common; 2) Insomnia prevalence is high; 3) Sleep architecture is abnormal; 4) NOD is commonly present; and 3) PR may improve sleep architecture, NOD, insomnia and OSA.


 

Translational Projects

$ 25,000

 

Awardee: Jared Young, PhD
Assistant Professor, Department of Psychiatry
Neurocognitive Effects of Nicotine Use in Schizophrenia: Parallel Human and Animal Studies

Abstract: In order to develop novel pro-cognitive therapies for schizophrenia, we have created and performed initial steps to validate a cross-species translational paradigm, the 5-choice continuous performance test (5C-CPT) that assesses attention and response inhibition in a consistent manner between that of humans and mice. Using this task, we propose to 1) identify regional attention-related brain response differences between patients with schizophrenia whom smoke and do not, and 2) test the effects of chronic nicotine on attentional performance in the Sp4 hypomorphic mouse model of schizophrenia. Convergent human and animal model studies have revealed that the Sp4 gene is strongly associated with cognitive deficits in patients with schizophrenia. Future studies will utilize identified regional abnormalities in patients to guide cerebral administration of selective nicotonic acetylcholine receptor agonists/antagonists in these mice.

Hypotheses: Schizophrenia patients would exhibit impaired 5C-CPT performance indicative of reduced sustained attention that is driven by poor target detection associated with reduced non-target-anteriorization (where neurophysiological biomarkers shift to frontal regions in the non-target vs. target conditions) which would be ameliorated in smokers vs. non-smokers. Moreover, Sp4 mice would exhibit homologous 5C-CPT behavioral performance in a pattern consistent with patients, which will also be improved after chronic nicotine.

 

Awardee: Michael McCarthy, MD, PhD
Assistant Professor, Department of Psychiatry
Pharmacogenetics in Treatment Refractory Depression

Abstract: Patients treated for depression vary in their response to medication due to differences in metabolism and physiology. While many depressed patients improve using standard approaches, only a fraction achieves full remission. Difficulty managing depression leads to protracted illness courses, multiple medication trials and an increased risk of suicide. In recent years, the prospect of personalized medicine has raised the hopes that some refractory depression cases can be helped using individually tailored approaches. However, few studies have investigated the practicality of this approach prospectively, in a “real world” clinic setting. We propose to use genetic testing in order to improve treatment outcomes among patients with treatment refractory depression (TRD), a collection of difficult to treat patients comprised of two sub-groups: complex major depressive disorder (MDD) and bipolar disorder (BD). We will also collect data before/after testing to determine patients’ views/concerns on pharmacogenetics and their expectations of treatment.

Aim 1: Compare outcomes of treatment for TRD guided by pharmacogenetic testing vs. treatment as usual.

Aim 2: Retrospectively identify the decision points where pharmacogenetic testing was the most useful.

Aim 3: Examine patient attitudes and expectations regarding pharmacogenetic testing in TRD.

 

Awardee: Sameh Ali, PhD
Assistant Professor, Department of Medicine
Markers of Oxidative Stress in Plasma and Cerebrospinal Fluid as Predictors of Sleep Disturbance in PTSD Subjects

Abstract: This proposal is based on preliminary work (Ali) showing that reactive oxygen species (ROS) exhibit daily rhythms in mice brains, and suggesting that ROS might be candidates for sleep regulation. Sleep disturbances are core symptoms of posttraumatic stress disorder (PTSD). Thus the primary goal of this pilot grant is to expand the current pre-clinical inquiry into a clinical setting and to gather sufficient pilot data for application for a translational NIMH R01 application. Data from this project will serve our longerterm translational goals, which are to identify the source(s), locations, and dynamics of ROS in brains of mice and humans.

Hypothesis and Rationale: Sleep difficulties, in particular poor sleep efficiency and nightmares, daytime fatigue, and cognitive and concentration complaints are common characteristics of PTSD. Therapeutic interventions to treat PTSD-associated sleep disorders and to ameliorate associated cognitive deficits are contingent upon understanding the neurobiological factors regulating sleep and cognition. One of the consistently reported neuronal responses to chronic stress in general and particularly in PTSD is the increased brain levels of pro-inflammatory cytokines including IL-1, IL-6, and TNF.  These cytokines are reported to modulate, and be modulated by ROS. Moreover, the same cytokines are known to elicit the nuclear translocation of NF| B, the primary nuclear factor linked to sleep regulation. We therefore hypothesize that: Levels of hydrogen peroxide as well as oxidized lipids and RNA/DNA in the cerebrospinal fluid (CSF) and plasma may predict the quality and duration of sleep in normal as well as PTSD subjects.

 

Awardee: Wesley Thompson, PhD
Assistant Professor, Department of Psychiatry
Improved Inferences in Dynamic Causal Modeling of Observational Data: Application to Breast Cancer Chemotherapy, Cognition and Sleep

Abstract: Breast cancer patients frequently complain of cognitive dysfunction during chemotherapy. Patients also report experiencing a cluster of sleep problems, fatigue and depressive symptoms during chemotherapy. It is possible that these symptoms mediate the effect of cancer treatment on cognition. Standard regression modeling cannot disentangle these complex associations. Causal modeling approaches (e.g., structural equations models) hold promise, but make un-testable modeling assumptions, and usually do not quantify the uncertainty in causal parameters. Moreover, the causal structure implied by a given covariance matrix generally includes an equivalence class of (many) causal models. We propose to apply novel artificial intelligence methods based on Pearl's Bayesian networks to model these variables.

Specific Aims

1. Develop Bayesian graphical network models to explore the mediating role of sleep/fatigue/mood on cognition prior to, during, and after chemotherapy.

2. Compute confidence intervals and upper bounds on  “casual” parameters obtained from the networks.

3. Determine a posteriori probability of multiple casual models, and use Bayesian model average methods to assess the weight of causal evidence.


 

Innovative Technology

$50,000

 

Awardee: Carl Stepnowsky, PhD
Assistant Adjunct Professor, Department of Medicine
Research platform for remote monitoring of health parameters

Abstract: We propose to advance the clinical facing components of the HH platform to yield a prepackaged service whereby the clinical researcher may define a mHealth study, select equipment, enroll patients, execute data collection and integrate the health data with their treatment protocol -- all with minimal additional cost and overhead in comparison to usual data collection methodologies.

Specifically we aim to develop the following:

1. Develop a HIPPA-compliant Cloud-based service platform to support multiple concurrent trials

2. Incorporate new sensors (those compatible with the ANT+ protocol)

3. Explore integration with the Velos eResearch web-based clinical trials system

4. Clinician/researcher training material and user guides

 

Awardee: Scott Matthews, MD
Associate Professor, Department of Psychiatry
Multimodal biomarkers of recovery from depression

Abstract: In order to develop an effective, safe and feasible EEG biomarker of treatment response with improved anatomic and clinical specificity, we propose:

(1) In subjects newly entering treatment for MDD, we will first use resting simultaneous EEG-fMRI to identify EEG correlates of default mode network (DMN) fMRI activity. In addition to preliminary and published data that DMN activity mediates depression pathophysiology and recovery, focusing on resting activity minimizes confounding effects from attention, motivation and familiarity with tasks, and maximizes feasibility of translation to larger clinical settings in the future.

(2) We hypothesize that, in contrast to subjects failing to respond to treatment, responders will exhibit distinct EEG correlates of changes in DMN activity specific to treatment response.

Our preliminary data demonstrate:

(1) Response to the antidepressant venlafaxine (Effexor) is associated with increased connectivity between DMN and superior and frontal cortical areas but decreased connectivity between DMN and limbic and posterior areas including the amygdala.

(2) In healthy controls undergoing resting simultaneous EEG-fMRI, we have successfully identified EEG correlates of DMN activity (scalp maps) compatible with generating the Response Map described above.


 

Community Pilot Projects

$15,000

 

Awardee: David Chang, PhD, MBA, MPH
Director of Outcomes Research, Department of Surgery Stronger Communities through Effective Mentorship and Trauma Prevention Program: A collaboration between the UCSD Department of Surgery, and San Ysidro High School

Abstract: We hope to advance the efforts to create healthier communities by addressing the educational goals of under-served communities, through a structured program of workshops focusing on stereotypes, cultural identity, self-esteem, and negotiation/conflict resolution. There will be three specific aims:

1. Evaluate Latino cultural identity issues.

2. Measure confidence levels in the Latino youth, and correlate improved cultural identity with improved self-confidence.

3. Evaluate whether increased confidence is associated with decreased beliefs supporting aggressive behavior. We hypothesize that youths with improved confidence will be better at resolving interpersonal conflicts and avoid turning to aggressive behavior to prove their selfworth.

 

Awardee: Jae Kim, MD, PhD

Associate Clinical Professor, Department of Pediatrics
Premature Infant Nutrition Post-discharge Collaborative Project

Abstract: The purpose of this project is to develop a network of community partners, including community-based clinicians, to identify barriers faced by mothers and community pediatric care providers in delivering optimal post-discharge nutrition for premature infants, with the ultimate purpose of developing intervention research aimed at achieving this goal. Aims

1) To conduct formative research to determine barriers faced by mothers and primary care providers in supporting optimal post-discharge nutrition in preterm infants, recognizing that human milk is optimal nutrition.

2) To establish a collaborative group of community-based clinicians along with other community partners that would form a community-based network to conduct the proposed project and future outpatient research in preterm infants.

 

Awardee:Carrie McDonald, PhD
Associate Professor, Department of Psychiatry
Neuropsychological and Neuroanatomical Profiles of Children with Temporal Lobe Epilepsy

 

Abstract: The current proposal aims to address some of the many unanswered questions regarding the cognitive morbidities of childhood TLE (Aim 1) and their relationship to underlying brain morphology (Aim 2). In doing so the proposed studies will provide insight into the impact that an early, ongoing neurological insult such as epilepsy can have on the development of brain and cognition.

AIM 1: Document the profile of neuropsychological deficits in pediatric TLE. Using a comprehensive battery of neuropsychological measures, the nature and extent of cognitive impairment in children with TLE will be investigated. Information about the cognitive profile of these children can provide information relevant for clinical treatment/intervention and for delineating more precisely the neurocognitive compatibility between adult and child TLE.

AIM 2: Investigate neuroanatomical abnormalities in pediatric TLE, and begin to determine how these abnormalities may predict neuropsychological dysfunction. The same group of children will undergo MRI, which will allow for detection of structural brain abnormalities, and determination of their relationship to neuropsychological function. Indices that provide important information regarding brain development, as well as the impact of disease processes, will be collected. These include quantitative structural indices of cerebral maturation, as well as indices reflecting the development of connections among cerebral areas. The former includes morphological measures of the cortical surface such as cortical thickness, while the latter includes measures derived from diffusion tensor imaging (DTI) that reflect the integrity of white matter tracts, such as fractional anisotropy (FA) and mean diffusivity (MD).