2011 Clinical Awardees
Awardee: Lisa Eyler
Neurocognitive Effects of Nicotine in Bipolar Disorder: Parallel Human and Animal Studies
Abstract: Background/Significance: Bipolar disorder (BD) is the sixth most disabling illness in the world, with functioning deficits that continue between mood episodes due to persistent impairments in cognition. Almost 50% of BD patients are smokers -- 2.5 times the rate of those without mental illness -- perhaps related to patients' attempts to alleviate symptoms, particularly attentional deficits, with nicotine. Few studies have examined the role of nicotine in BD cognition, and none has compared attention-related brain systems between BD smokers and non-smokers. Nicotine's role has been studied more extensively in animal tests of cognitive functioning, but no study has examined effects of chronic nicotine use on attention and inhibition in a genetic mouse model with relevance to BD. Aims: In order to develop novel pro-cognitive therapies for BD, we have created and validated a translational paradigm, the five choice continuous performance test (5C-CPT), that assesses attention and response inhibition similarly in humans and mice. Using this, we aim to 1) discover regional attention-related brain response differences between BD smokers and non-smokers, and 2) test the effects of chronic systemic nicotine on attentional performance in a dopamine transporter (DAT) gene knockdown mouse model of BD. In future studies, regional abnormalities found in the human imaging study will guide targeted cerebral administration of selective nicotonic acetylcholine receptor agonists/antagonists in the mouse to test their cognitive effects. Hypotheses: BD smokers will engage a larger network of attentionrelated brain regions than BD non-smokers. DAT knockdown mice exposed to nicotine will have better vigilance and fewer inhibitory errors compared to placebo-injected knockdown mice, and nicotine's benefits will be greater in knockdown than wildtype mice. Methods: Both versions of the 5C-CPT involve an array of five circular visual stimuli that can be illuminated singly or in unison. When a single stimulus is illuminated, a response to that location is required; when all stimuli are illuminated, the participant must withhold responding. Measures include hit and false alarm rates, vigilance, accuracy, bias, and reaction times. Human Imaging: 10 smoking and 10 non-smoking remitted BD patients (age 30-45) will be recruited from an ongoing study. Functional magnetic resonance imaging (fMRI) will be used to compare whole-brain response during the human 5C-CPT (vigilance and inhibitory responding) between smokers and non-smokers, covarying for any differences in clinical and demographic variables. Mouse Model: Starting at 24 weeks of age, nicotine or placebo will be administered daily at a dosage of 10 µg/kg for 14 days to DAT knockdown mutant mice or wildtype littermates (n=8 per group). DAT knockdown mice exhibit a pattern of hyperexploration and increased risk taking that is consistent with BD patients. Performance will be tested on days 14 and 15 using the rodent 5C-CPT challenges, and group differences in vigilance, false alarms, and reaction time will be analyzed using a two-way ANOVA, with Tukey post hoc analyses performed on significant effects observed.
Awardee: Hal M. Hoffman, MD
Associate Professor, Department of Pediatrics
Genetic and Molecular Basis of Familial Atypical Cold Urticaria
Abstract: Cold urticaria is characterized by pruritic hives and swelling upon exposure to cold. This condition may present in childhood or adulthood and can be debilitating as some patients develop severe extremity swelling after briefly touching cold objects and oropharyngeal angioedema after drinking cold liquids. There is also a significant risk of death from systemic anaphylaxis in patients who swim in cool water. Diagnosis is often made by a positive ice cube test, in which ice is placed on the forearm for 3-10 minutes, resulting in the development of a pruritic wheal at the site within a few minutes. However, there are some patients with an atypical form of cold urticaria who have similar symptoms upon generalized cold exposure. These patients have a negative ice cube test. (Wanderer and Hoffman 2004)
Familial Atypical Cold Urticaria (FACU) is a rare condition with an autosomal dominant mode of inheritance. We recently characterized this disorder, which begins in early childhood and persists throughout life with significant impact on affected patients (Gandhi et al 2009). We have identified 4 FACU families with cold sensitivity to a unique temperature range, as there is no response to the ice cube test. Genetic mapping of two of the families has identified a 3.5 MB region on chromosome 16q containing several interesting candidate genes.
Mast cells and histamine have been implicated in the pathogenesis of cold urticaria and FACU, as suggested by pathologic studies and the therapeutic response to antihistamines. However, the mechanism of cold sensitivity is not understood and current therapies are inadequate. Neurons have been shown to sense temperature via Transient Receptor Potential (TRP) channels, (Bandell et al 2007) but the process in immune cells remains to be elucidated. We hypothesize that specific TRPs are involved in the mast cell response to cold.
Awardee: Amy E. Lansing, PhD
Assistant Professor, Department of Psychiatry
Hearing Loss, Middle Ear Status & Auditory Processing Deficits in Detained Girls.
Abstract: Few facts about delinquency are more robust than the overrepresentation of ethnic minorities and lower SES individuals in correctional populations. Minorities and youth with disabilities are over-represented in school suspensions/expulsions, drop-out and the Juvenile Justice System [JJS], with >33% of incarcerated youth having an identified mental health/educational disability requiring services (Individuals with Disabilities Education Act). Girls are the fastest growing, but least studied, segment of arrested youth, with 75-95% having childhood maltreatment histories. The social and fiscal costs associated with delinquency are not limited to the JJS. Antisocial girls demonstrate significantly elevated rates of medical problems; lower body mass index; tobacco dependence; physical injuries; early pregnancy; risky sexual/health practices, psychiatric/substance use comorbidity, school dropout, welfare dependency and mortality. Unfortunately, detained girls appear to be the most in need of services but remain the most underserved. This constitutes a public policy crisis related to health disparities and questionable implicit disability practices.
Language deficits are the most prevalent cognitive problems among delinquents. Language disorders are associated with a vast array of learning, social and behavioral problems - with a longstanding link to delinquency - yet we understand little about this complex interplay. Notably, the incidence of hearing loss in adult prisoners is ~30%, with predominant middle ear abnormalities. Peripheral auditory deficits (PAD: hearing acuity, middle ear function, signal reception) can contribute to impoverished language and poor social skills yet we lack data on incarcerated youth and hearing evaluations rarely occur. The few available data are exclusive to boys and small samples. In order to intervene effectively in the language deficit, academic
dysfunction and delinquency spiral, we must bring the best practices to bear in treating these vulnerable youth. Differentiating between PAD and auditory processing deficits (APD, acoustic discrimination etc.) will provide insight into the potential benefit for amplification and remediation strategies – particularly among mildly hearing impaired youth.
Awardee: Lisa T. Eyler, PhD
Associate Professor, Department of Psychiatry
Neurocognitive Effects of Nicotine Use in Bipolar Disorder: Parallel Human and Animal Studies
Abstract: Bipolar disorder (BD) is the sixth most disabling illness in the world, with functioning
deficits that continue between mood episodes due to persistent impairments in cognition. Almost 50% of BD patients are smokers -- 2.5 times the rate of those without mental illness –- perhaps related to patients’ attempts to alleviate symptoms, particularly attentional deficits, with nicotine. Few studies have examined the role of nicotine in BD cognition, and none has compared attention-related brain systems between BD smokers and non-smokers. Nicotine’s role has been studied more extensively in animal tests of cognitive functioning, but no study has examined effects of chronic nicotine use on attention and inhibition in a genetic mouse model with relevance to BD.
Awardee: Randy A. Taplitz, PhD
Associate Professor, Department of Medicine
The Role of Type 1 Interferon in Allogeneic Stem Cell Transplant
Abstract: Allogeneic stem cell transplant (SCT) is a life saving therapy for patients with leukemia and lymphoma. Cytomegalovirus (CMV) is an immunomodulatory virus, which reactivates commonly in SCT recipients and significantly contributes to transplant mortality. Forty percent of cancer patients receiving SCT at this institution develop cytomegalovirus infection (manuscript in preparation).Risk factors for CMV infection include recipient CMV serostatus, older age, acute graft versus host disease (GVHD) and unrelated transplant. Donor serostatus and chimerism (proportion of hematopoietic cells of host and donor (origin) may also be associated with CMV infection, but are less well delineated. SCT recipients remain profoundly immunosuppressed for 1 or more year(s) post transplant. Type 1 Interferon(IFN) is an immune regulatory cytokine that is essential for host protection and provides key survival signals for T cells. Mouse models have clearly demonstrated that an absence of IFN leads to catastrophic apoptosis of lymphocytes, loss of T cell trafficking and deregulation of lymphoid tissue.
Objective: To delineate the role of certain immunologic factors (IFN and chimerism) and donor CMV serostatus on CMV infection, GVHD and engraftment in allogeneic SCT.
Hypothesis: Patients with full donor chimerism, IFN gene expression and SCT from CMV seropositive donors will have improved CMV virus control upon reactivation as measured by peak and duration of CMV viremia and multiple reactivations. Early mixed chimerism will be predictive of CMV reactivation. Specific aims:
Aim 1: To characterize the effect of IFN gene expression on GVHD, engraftment and the control of CMV reactivation in allogeneic SCT recipients.
Aim 2: To evaluate the effect of donor CMV serostatus and chimerism on IFN gene expression and CMV reactivation.
2011 Translational Technology Awardees
Awardee: Jenny M. Kim, MD
Associate Professor, Department of Pediatrics
Biomarkers of Human Sickle Cell Disease
Abstract: Biomarkers of Human Sickle Cell Disease (SCD) is a three-way collaboration between Jenny Kim, Director of the Sickle Cell Program at Rady Children’s Hospital (RCH); Joel Linden, who studies activation of iNKT cells in a mouse model of SCD; and Kelly Frazer, who is expert in RNA-seq and bioinformatics. This is a new research direction for all three investigators. SCD is caused by a point mutation in the sixth codon of the β-globin gene resulting in replacement of a glutamic acid residue by valine1. Sickle RBCs mechanically obstruct capillaries and trigger recurrent episodes of disseminated microvascular ischemia/reperfusion injury2. We have discovered that a minor lymphocyte cell type, iNKT cell, amplifies inflammation and injury in the NY1DD mouse model of SCD. Blocking the activation of these cells greatly reduces injury. iNKT cells are activated by glycolipid self-antigens and cytokines that are produced in ischemic tissues. Activated iNKT cells transactivate other leukocytes. We recently discovered that people with SCD have elevated numbers of activated iNKT cells in their blood. Here we propose basic and clinical experiments to address two fundamental questions: 1) How do purified human iNKT cells respond to activation and inhibition; and 2) how are iNKT cells changed during pain episodes in SCD patients?
Awardee: Alessandra Sacco, MD
Clinical Professor, Dept. of Orthopedics
Role of telomere shortening in human Duchenne Muscular Dystrophy
Abstract: Duchenne Muscular Dystrophy (DMD) is a devastating X-linked muscle degenerative disease which affects ~1/3500 of all males born. Despite the underlying genetic defect having been identified over two decades ago, there is currently no effective cure available to patients. The disease is caused by a mutation in dystrophin, a cytoskeletal protein that is essential for the membrane stability of multinucleated myofibers in skeletal muscle. Absence of dystrophin results in increased fragility of the sarcolemma, leading to progressive loss of muscle function, paralysis and death in the third decade of life.
The cause of the failure in DMD skeletal muscle to repair damaged tissue is currently unknown. We hypothesize that the regenerative potential of muscle stem cells (MuSC) is progressively exhausted with time in DMD patients, due to critical telomere shortening. We tested this hypothesis in mice by crossing dystrophic mdx mice with mice lacking telomerase activity. This novel mouse model shows that dystrophin deficiency coupled with telomere dysfunction recapitulates the severe phenotypic characteristics of human DMD. These mice exhibited profound muscle weakness, elevated serum creatine kinase levels, progressive loss of muscle mass, and shortened life-span. MuSC exhibited a severe proliferation deficit both in vitro and
in vivo. Critical telomere shortening was detected in muscle cells already at young age. These findings support our hypothesis that DMD is initially due to the genetic defect in dystrophin, but progressively becomes a stem cell defect as regenerative potential is exhausted with time.
Awardee: Jean Wang, PhD
Distinguished Professor of Medicine and Biology
Targeted nanosomal delivery of Imatinib to ameliorate renal damage from cis-platinum therapy for cervical cancer
Abstract: Cisplatin is a widely used and highly effective cancer chemotherapeutic agent. The main dose-limiting side effect of cisplatin is nephrotoxicity. The incidence of renal insufficiency in more recent experience using saline hydration and diuresis, is in the range of 20–30% of patients. Typically, the onset of renal insufficiency begins several days after the dose of cisplatin, and recovery of renal function usually occurs over a period of 2–4
weeks, though more protracted courses, as well as lack of recovery are reported. Progressive and permanent
nephrotoxicity can result with successive treatment courses despite preventative measures. A number of risk factors for cisplatin nephrotoxicity have been identified including female sex, older age, smoking, pre-existing renal dysfunction, and hypoalbuminemia.
The proposed research is directed at developing a kidney-targeted formulation of imatinib, an FDA-approved tyrosine kinase inhibitor that can inhibit among others the cellular ABL kinase.
It is our hypothesis that inhibition of ABL tyrosine kinase in the kidney can reduce nephrotoxicity induced by the chemotherapeutic drug cisplatin. This hypothesis predicts that kidney-targeted imatinib would ameliorate renal damage in cancer patients receiving platinium-based therapeutics. The Imatinib will be preferentiall delivered to the kidneys with 100 nm liposomal nanoparticles that include a cross-linked nanogel core. This core structure allows efficient loading of virtually any drug chemotype.
Ample evidence, including our own indicates a robust accumulation of untargeted liposomes within all compartments within the kidney.
The hypothesis that kidney-targeted inhibition of cellular ABL tyrosine kinase can reduce platinum-induced nephrotoxicity is supported by a body of research conducted in the PI’s laboratory, which has been studying the role of nuclear ABL in DNA damage response for more than a decade. The PI discovered that cisplatin activates the nuclear ABL tyrosine kinase to stimulate p53-independent, but p73-dependent apoptosis, in human cancer cells. The Wang laboratory then engineered a mouse strain, in which the three nuclear localization signals (NLS) in the ABL protein are inactivated by substitution mutations using the knock-in technology. Experimenting with mouse ES cells expressing the NLS-deficient ABL protein from this
Abl-μNLS allele, the PI uncovered genetic evidence to support the conclusion that activation of the nuclear ABL tyrosine kinase is an important mechanism underlying cisplatin-induced apoptosis. The Wang laboratory investigated the response of
Abl-μNLS homozygous mice to cisplatin, focusing on the kidney tissue, because cisplatininduced nephrotoxicity is a dose-limiting adverse effect in cancer therapy. Cisplatin-induced renal tissue damage was greatly reduced in the Abl-μNLS-homozygous mice when compared to
Because ABL tyrosine kinase mediates cisplatin-induced apoptosis in renal tubule cells and in tumor cells, a kidney-targeted liposomal nanoparticleformulation of imatinib is required to achieve the goal of protecting the kidney tissues while allowing the drug to kill tumor cells. The proposed pilot study will test a series of imatinib formulations in the
Abl-μNLS-homozygous mice. Our hypothesis predicts that the targeted inhibition of ABL tyrosine kinase in the kidney would provide n the
Abl-wt mice a level of protection that iscomparable to that observed with the
Awardee: Karen Christman, PhD
Assistant Professor of Bioengineering
Injectable autologous scaffold for treating myocardial infarction
Abstract: Despite recent advances in tissue engineering, heart failure following a myocardial infarction (MI) continues to be the leading cause of death in the U.S., with end-stage heart failure patients still relying on donor hearts. Therefore, our long-term goal is the translation of new, minimally invasive tissue-engineered therapies for the treatment of MI. In situ cardiac tissue engineering using injectable biomaterials scaffolds is an attractive alternative approach since potential therapies could be delivered minimally invasively. As a material only therapy, the material is injected into the infarct, and can serve to increase cell migration into the infarct area, including neovascularization, to thicken and support the left ventricular wall, or both. New decellularized matrices are offering exciting new scaffolds, including injectable ones, that retain the complexity and biochemical cues of native extracellular matrix (ECM); however, historically, the tissue decellularized to make patches and grafts, or produce M hydrogels has been necessarily xenogeneic or allogeneic as one’s own small intestine submucosa, bladder, and cardiac tissue cannot be harvested in sizeable quantities without detriment. Yet, if the endogenous repair shown with these ECM scaffolds – including cell infiltration andneovascularization – can be achieved using a scaffold derived from an autologous source, it would provide a faster route to clinical translation, reducing regulatory concerns and avoiding any ethical, immunogenic, or disease transfer concerns associated with xenogeneic or allogeneic sources. We have recently developed an injectable form of pericardial matrix, which has the potential to be an injectable, autologous scaffold for tissue engineering since the pericardium can be removed without adverse consequences. We have shown that this new material gels in the myocardium and promotes cell infiltration and neovascularization. We thus hypothesize that decellularized, injectable pericardial matrix can be used as an autologous scaffold for myocardial tissue engineering to increase endogenous cell recruitment and protect against post-MI negative left ventricular remodeling and cardiac dysfunction. We will therefore address the following specific aims in this project: 1) To determine the influence of an injectable human pericardial matrix scaffold on negative left ventricular remodeling, cell infiltration, and cardiac function post-myocardial infarction in a rat MI model, and 2) To evaluate percutaneous delivery of autologous pericardial matrix in a pig model. Aim 1 will allow us to assess the feasibility of utilizing the injectable pericardial matrix scaffold for preserving cardiac function post- MI using echocardiography and MRI, while Aim 2 will allow us to test the feasibility of collecting and delivering the autologous pericardial scaffold using the appropriate clinical techniques/procedures. The proposed project will be accomplished through an interdisciplinary, translational research team of investigators that has already worked together to generate preliminary data, is uniquely positioned to carry out this project, and possesses the necessary expertise and tools in biomaterials and cardiac physiology, pathology, and surgery. The objective of this project is the development of a new autologous tissue-engineered therapy for treating MI, with the next steps being a pivotal large animal functional study and clinical translation.
Awardee: James Hagood, MD
Professor and Chief, Pediatric Respiratory Medicine
Lung-specific targeting of antifibrotic therapies
Abstract: Idiopathic pulmonary fibrosis (IPF) is one of the deadliest and most recalcitrant pulmonary disorders. Despite recent coordinated attempts to rapidly translate biologically promising therapies into effective treatments in IPF, there have been no major clinical breakthroughs. In this project we will translate a novel mechanism for delivery of therapeutics for treatment of IPF and other diffuse lung diseases. Many therapies for IPF and other diffuse lung diseases have failed because of poor penetration into the lung through the endothelial cell (EC) barrier. Aminopeptidase P (APP) is specifically enriched in lung EC caveolae, enabling lung-specific targeting of intravascularly injected APP antibodies (mAPP). These are actively and specifically pumped rapidly across the EC barrier via caveolae to reach the lung interstitial spaces. In rats, conjugation of anti-transforming growth factor beta (a-TGF-β) to mAPP dramatically reduces collagen deposition in the bleomycin model of pulmonary fibrosis compared to a-TGF-β alone. Systemic (off-target) delivery of mAPP-conjugated therapies is almost negligible. Lung-specific targeting also allows higher effectiveness at a lower total dose.
Because of the futility of existing treatments, there is an urgent need to rapidly translate these findings into clinical applications; to that end, additional preclinical studies and validation in human tissues are required. The overall goal of this proposal is to determine the feasibility of using a novel mechanism of lung-targeted delivery of existing compounds in IPF, a major lung disease that lacks effective therapies.
Hypothesis: Lung-specific delivery of anti-fibrogenic therapies is feasible and will result in enhancement of their therapeutic efficacy.
Awardee: Suzi Hong, PhD
Assistant Professor of Psychiatry
Validation of Flow Cytometric Analysis of Beta-adrenergic Receptor Expression on Blood Leukocytes in the Healthy and Heart Failure Patients
Abstract: The impact of sympathetic activation on cardiovascular pathology is well documented. Patients with cardiovascular disease (CVD) have been shown to exhibit elevated levels of catecholamines and dysregulation in beta-adrenergic receptor (β-AR) physiology1-3. These findings led to widely utilized β-AR blockade treatment in patients with CVD including heart failure (HF). Although the findings of AR density and sensitivity of various tissues provided initial insight into AR physiology, the complexity of investigating β-ARs on central organs in humans is evident. As circulating leukocyte β2-AR expression reflects other tissue expression levels, β-AR expression on blood leukocytes is assessed to examine one’s β-AR activity, using radioligand-binding (RLB) assays. This method is sensitive in measuring density and affinity of β-ARs, but with a number of disadvantages: it’s 1) labor-intensive, requiring multiple assay steps, 2) requires a large blood volume (~40mL), reducing clinical applicability, and 3) utilizes a radioisotope (125I), carrying radioactivity-related risks.
Awardee: Victoria Risbrough, PhD
Assistant Professor in Residence, Psychiatry
COMT val/met polymorphism effects on novelty-seeking: Developing a mouse model of Bipolar Disorder
Abstract: Animal models of disease are critical to the development of new treatments, and ideally there should be a high degree of homology between the preclinical (animal) measures used and the corresponding clinical (human) constructs of interest. This homology is difficult to achieve in animal models of psychiatric conditions, because animals cannot report about psychosis, mood changes, etc. Especially problematic is the development of models for Bipolar Disorder (BD), where the challenge is to recreate a phenotype that is present across all phases of the illness. Novelty-seeking, or a tendency to seek out new and unfamiliar situations, is an essential feature of BD even in remitted phases and is thought to be influenced primarily by dopamine (DA)-related genes. Unlike other cardinal symptoms of BD, novelty-seeking can be quantified in both humans and animals using parallel methodologies, such as the “open field” paradigm termed the Behavioral Pattern Monitor (BPM) that is applied in humans and rodents. Thus the measurement of novelty seeking can be subjected to translational research, which is hoped to lead to the eventual development of much-needed new treatments for BD. This technology was developed in humans by our proposed clinical expert, Dr. Minassian and her colleagues Drs. Geyer and Perry at UCSD. Their preliminary work suggests that the gene that codes for the catechol-O-methyltransferase (COMT) enzyme influences novelty-seeking behavior in BD subjects such that the low-activity allele of the Val158Met polymorphism, Methionine (Met), is associated with greater novelty-seeking in manic patients in a human version of the BPM. They are funded to examine the effects of high DA levels on novelty-seeking in the human BPM via DA agonist challenges in healthy controls with either COMT genotypes, to determine whether high DA tone in humans mimics the high novelty-seeking phenotype expressed by BD subjects. Drs. Risbrough and Zhou have created a novel line of “knock-in” mice that express the human COMT gene with either the Valine (Val) or Met single nucleotide polymorphism. These mice offer a unique opportunity to identify neural circuits and substrates mediating humanized COMT Val158Met control of exploratory and novelty-seeking behavior both in the healthy and pathological state. We propose studies in our mice of DA agonist effects on exploration and novelty-seeking in the mouse BPM, in parallel to the ongoing human studies. We predict that both mice and humans that carry the COMT Met allele will exhibit increased exploratory and novelty-seeking behavior compared to Val carriers under conditions of high cortical and striatal DA tone (e.g., DA agonist treatment). Such a response would mimic the effects of the COMT gene on exploration in manic BD subjects, validating these mice as a potential model for COMT contribution to mania-related behaviors. The next step will be to determine if COMT genotype modulates treatment efficacy (e.g., antipsychotics vs. mood stabilizers) in this model. This application hopes to address what has been a difficult challenge in neuroscience: the refinement of valid genetic and pharmacological animal models of BD which are critical to the generation of new, perhaps gene based treatments.
2011 Innovative Technology Awardees
Awardee: Dena Rifkin, MDAssistant Professor
Real-time wireless blood pressure monitoring for kidney disease
Abstract: Chronic kidney disease (CKD) and hypertension are major public health problems in older adults; 25-40% of individuals over the age of 60 have evidence of CKD and 65-95% of these individuals have high blood pressure. Control of hypertension is a vital part of CKD care, as the risk of cardiovascular disease is extremely high.
However, reliance on clinic blood pressure readings is an inadequate means of optimizing blood pressure (BP) control in CKD patients. Masked hypertension (hypertension outside of clinic) is frequent, and associated with adverse cardiovascular outcomes. CKD patients also have vascular calcification and episodes of relative hypotension, a major risk for falls and fractures. Complicating this situation further, CKD has strong associations with frailty, cognitive impairment, and polypharmacy, making blood pressure even more difficult to manage. Efforts to improve BP management have included home BP monitoring programs, behavioral coaching, or reminder systems to improve adherence. However, these efforts have been suboptimal due to reliance on 1) high level of patient adherence with recording BP data and 2) inefficient data flows (patient communicating data via telephone, fax or hand-carrying BP logs). There is evidence that IT interventions are effective, but most IT interventions require Internet access and greater computer literacy than older kidney disease patients possess. As a result, home BP readings are often not recorded, forgotten, difficult to interpret, or out-of-date by the next clinic visit.
Awardee: Steven J. Bark, PhD
Assistant Professor, SCHOOL OF PHARMACY/PHARMACEUTICAL SCIENCE
Molecular Basis of Microglial Activation by the Fractalkine Receptor, CX3CR1
Abstract: This project seeks a comprehensive understanding of the role of fractalkine receptor (CX3CR1) signaling mechanisms underlying microglial activation and long-term pain to identify new and more effective avenues for therapeutic intervention. To achieve this objective, we will uncover the proteins activated by CX3CR1 in response to nerve injury. Because CX3CR1 is directly involved in neuropathic pain progression,1,2,3 proteins activated by this receptor are potential targets for therapeutic intervention. We have established quantitative mass spectrometry methods that can be applied to define protein-signaling events initiated by activated CX3CR1, in a similar manner reported for CXCR2.4 The interdisciplinary nature of this research involves collaborations with Dr. Tracy Handel for cytokine receptor cell biology, Dr. Tony Yaksh for in vivo neuropathic pain models, and Dr. Vivian Hook for biochemistry studies by mass spectrometry.
Awardee: Rebecca J. Theilmann, PhD
Assistant Professor, Department of Radiology
Quantitative Magnetic Resonance Assessment of Secretions in Cystic Fibrosis Airways
Abstract: Cystic Fibrosis (CF) is an inherited disease associated with a severely impaired mucociliary clearance that leads to chronic polymicrobial airway biofilm infection, inflammation, airway remodeling and eventually respiratory failure in almost 85% of patients. Maintenance therapy includes airway clearance treatments, anti-inflammatory therapy along with inhaled antibiotics, hypertonic saline and rhDNase. Intermittent exacerbations are treated with increased airway clearance techniques and systemic antibiotics. Patients are followed clinically, radiographically and with lung function studies and microbial cultures. The clinical therapy and translational investigations have a critical need for a quantitative measure of the biofilm that could be used repeatedly. Lung function studies clearly lack sensitivity. CT scans are very useful but cannot be used repeatedly. Standard chest MRI lack the anatomic resolution needed to quantify the biofilm.
Awardee: William Song, PhD
Assistant Clinical Professor of Radiation Oncology
Development of novel 4D imaging framework for liver cancer radiation therapy
Abstract: Liver cancer, whether primary or metastatic in origin, causes substantial morbidity in a significant number of patients. Especially, the liver metastasis is very common life-threatening event where, among all patients that die of cancer, up to 70% has liver metastasis at autopsy. In addition to this grave prognosis, currently, there’s no satisfactory treatment available for this disease. This was the motivation behind the recent adoption of stereotactic radiation treatment protocol at UCSD with hypo-fractionated regimen for metastatic liver cancer management. Unfortunately, however, radiation therapy of liver cancer is perhaps the most challenging of all sites due to the fact that 1) breathing-induced tumor motion is difficult to characterize during treatment due to the lack of time-resolved imaging (i.e., four-dimensional imaging) which causes motion-related imaging artifacts, and 2) liver cancer unfortunately has similar X-ray attenuation characteristics as the normal liver surrounding it, making it difficult to discern the tumor shape and location from standard cone-beam CT (CBCT) imaging. Both of these problems directly cause inaccurate radiation delivery to the intended tumor volume, which may lead to compromised treatment effectiveness and increased normal tissue side effects.
2011 Community Awardee
Awardee: Lisa Madlensky, PhD
Associate Professor, Department of Family and Predentive Medicine
Developing a Community-Based Cancer Genetics Research Project with the Chula Vista Community Collaborative
Abstract: This pilot project is intended to serve as a developmental platform for a future promotora-based community intervention that aims to improve the collection of cancer family history information. Prior research and clinical anecdotal evidence suggest that there are cultural barriers to obtaining accurate family cancer history information among Latino cancer patients and families. An accurate cancer family history is critical in determining appropriateness of genetic testing (e.g. for BRCA1/2 mutations that predispose to breast and ovarian cancers). The family cancer history can also be used to tailor screening and surveillance guidelines for families who may be at increased risk of certain cancers (e.g. more frequent colonoscopic surveillance among patients with a family history of colon cancer). Novel culturally-appropriate methods for collecting accurate family cancer history information are needed.
The Chula Vista Community Collaborative (CVCC) Promotora Program is an established program with the mission of assisting community residents in achieving optimal levels of health, well being and community safety through neighborhood and school outreach strategies that focus on prevention and education.
Promotoras are local Spanish-speaking residents who serve as liaisons between their community and integrated health and family support. As liaisons, they often play the roles of advocate, educator, mentor, outreach worker, role model, translator and more. The Promotora model is based on a Latin American program-type that reaches underserved populations through peer education. This means that promotoras come from the same neighborhood, speak the same language, and usually share some of the same or similar life experiences as the community members they serve.