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2014-15 Award Recipients

Karen Andes, PhD
Global Health| Rollins School of Public Health
Growing Up on the Margins: Exploring Pathways for Positive Transitions to Adulthood in an Urban Slum in Asuncion, Paraguay

Rapid Urbanization is one of the key characteristics of 21st century cities worldwide. As city populations grow more rapidly than space and infrastructure can accommodate, poor families settle in informal communities characterized by poor living conditions, inadequate infrastructure, crime and violence, and poor health outcomes. While these populations tend to be overwhelmingly young, little research has focused squarely on how youth who live in marginalized communities might achieve successful transitions to adulthood despite being met by significant obstacles. The qualitative study proposed here seeks to understand how local youth perceive negative community-level factors (e.g. limited educational opportunities, poor employment prospects, and high risk environments for early pregnancy and HIV/STI transmission, alcohol/ substance abuse, crime/delinquency and violence), and how those factors shape their ability to achieve positive transitions to adulthood (education/employment, marriage/childbearing, community/civic engagement) in a "slum" community of Asuncion, Paraguay. This exploratory research project will conduct four focus group discussions and eight life history interviews with young adults aged 18-30 who are "positive deviants" - demonstrating positive trajectories on pathways to adulthood even in the face of adversity - in the Banado Sur community of Asuncion. The data collected here will result in at least three publishable manuscripts while also laying the foundation for a longitudinal study to be submitted as an R01 proposal to the NIH.

Carolyn Drews-Botsch, PhD
Epidemiology| Rollins School of Public Health
Quality of Life in School-Ages Children Treated for Unilateral Congenital Cataract

The Infant Aphakia Treatment Study (IATS) was an NIH-funded, randomized clinical trial designed to assess the best mode of treatment for children who are born with a unilateral congenital cataract. This study found that children receiving an intraocular lens at the time of cataract extraction did not affect visual acuity at 54 months of age, but those treated with an IOL required more surgeries and had more adverse events. Based on these results, the investigators have suggested that, in most cases, it is prudent to refrain from implanting an IOL in these infants. However, additional questions remain regarding the long-term impact of these two treatments on the lives of these children Understanding the impact of these conditions on quality of life outcomes, and whether initial treatment affects these outcomes will improve the management of these conditions by providing families, educators, and health care providers with information to provide anticipatory guidance and to make appropriate treatment decisions. The purpose of this pilot study is to determine the feasibility of assessing of administering four brief assessments of quality of life to school-aged children and their parent in an eye clinic setting using auxiliary personnel. The pilot survey will administer four standardized questionnaires to assess health-related quality of life (HRQoL), vision-related quality of life (VRQoL), behavior problems, self-esteem, participation in activities, reading speed and comprehension, and parenting stress to 25 school-aged children treated for unilateral cataract and their caregivers. The outcomes in these children will be compared to 25 children with normal vision and to 25 children with amblyopia from other causes. The results of this pilot study will be used to support an NIH application to conduct a more comprehensive survey of the quality of life of 10-year old children who were treated for congenital cataracts in the Infant Aphakia Treatment Study.

Charles Easley, PhD
Cell Biology| School of Medicine
Effects of Flame Retardant Exposure on Human Spermatogenesis Using a Novel in vitro Model

Human spermatogenesis is a highly organized and regulated process that is susceptible to environmental toxicants such as endocrine-disrupting chemicals and medical treatments. Environmental influences and insults by toxicant exposure during early development or post-puberty can lead to impaired spermatogenesis or sterility/infertility. Understanding how certain chemicals disrupt spermatogenesis during various Windows of Susceptibility (WOS) is critical for determining how environmental and industrial toxicants contribute to impaired fertility. Furthermore, these toxicants can potentially induce epigenetic alterations that contribute to disease phenotypes in offspring and thus have transgenerational consequences such as increased risk of producing offspring with neurological disorders, cardiac malformations, limb defects, and other developmental deficiencies that lead to debilitating disorders. One such class of toxicant is flame retardants, which are widely used in several consumer products including electronics, furniture, children's clothes and accessories. Because flame retardants are often not covalently linked to their products, these chemicals leach out into the environment and persist causing decades of exposure. Flame retardant exposure has been linked to some human diseases including Parkinson's disease, but the effects of exposure on spermatogenesis are just now being investigated, and their impact on sperm production or the epigenetic state of sperm is poorly understood. This proposal seeks to utilize a novel in vitro model of human spermatogenesis to examine the effects of flame retardants on various windows of susceptibility during spermatogenesis to begin to uncover how exposure to flame retardants may negatively impact human spermatogenesis.

Ross Fasano, MD
Clinical Pathology| School of Medicine
Effects of Acute Chest Syndrome-related intravascular hemolysis on pro-inflammatory immune priming for alloimmunization in Sickle Cell Disease patients

Ongoing inflammation during transfusion has been shown to affect RBC alloimmunization in murine models. We previously demonstrated that recipient pro-inflammatory state, most notably acute chest syndrome (ACS) at time of transfusion, directly impacts RBC alloimmunization in a large human sickle cell disease (SCD) cohort. However, the immunologic effects of ongoing inflammation during transfusion remain unclear. It has been suggested that lymphocytes of non-alloimmunized SCD patients are more polarized toward a regulatory state than alloimmunized patients. Plasma heme (hemin), a potent inflammatory agonist, is the major source of oxidative stress in SCD and other conditions associated with intravascular hemolysis. Because SCD patients have overwhelmed hemin scavenging systems, they are particularly dependent on heme-oxygenase-1 (H0-1) up-regulation to clear hemin and minimize its pro-inflammatory effects. Hemin has been shown in vitro to induce differential polarization of CD4+ T-lymphocytes in alloimmunized and non-alloimmunized SCD patients. Our study will provide in vivo data on the effects of ACS-related intravascular hemolysis on pro-inflammatory immune priming for alloimmunization in SCD patients, which will support or refute the notion that a direct correlation exists between SCD pathology associated with worsened hemolysis (i.e. ACS),pro-inflammatory immune polarization through heme/H0-1 dependent effects on lymphocytes, transfusion, and ultimately RBC alloimmunization risk.

Veronika Fedirko, PhD
Epidemiology | Rollins School of Public Health
Gut Microbiome and Metabolome in Phenylketonuria

Phenylketonuria (PKU) is a rare autosomal recessive inherited metabolic disorder affecting approximately one in 10,000 live births. Management of PKU is largely accomplished by diet manipulation to severely restrict dietary phenylalanine (Phe) intake, and more recently included drugs (Kuvan® and PEG-PAL) that are usually used in combination with the Phe-restricted diet. Non-compliance to diet has been linked to elevated plasma Phe concentration and adverse health effects throughout the life span. Alternative approaches to reduce the burden of the difficult and restrictive diet on patients and their families, lower Phe levels, and improve health outcomes are urgently needed. Limited evidence suggests an important role for the gut microbiome in Phe metabolism; however, it is unknown whether 1) the gut microbiome diversity and composition differs among patients with PKU (overall and by treatment regimens) compared to healthy individuals, 2) the gut bacteria could be manipulated to lower Phe levels and/or be used to relax the dietary restrictions. Therefore, we will investigate the gut microbiome in combination with stool metabolome in adolescent girls and young women with PKU (n = 30) in a pilot study within a weeklong metabolic camp. We will collect a stool sample before and after the education intervention, and will analyze the samples to characterize the stool bacteria using 16S rRNA gene sequencing, and fecal metabolome using high-resolution metabolomic profiling with liquid chromatography-Fourier transform mass spectrometry (LC-FTMS). Understanding the diet-gut microbiome-host interaction may help with managing health outcomes and developing treatment regimens for individuals with inherited metabolic disorders including PKU. The preliminary data we obtain will be used to apply for a NIH R01 to conduct a full-scale study.

Jennifer C. Felger, PhD
Psychiatry & Behavioral Sciences | School of Medicine
Inflammation-related Alterations in Corticostriatal Connectivity in Depression: Reversal with Levodopa

Evidence suggests a relationship between inflammation and depression. For example, numerous studies have reported that inflammatory markers, including inflammatory cytokines and acute-phase proteins such as C-reactive protein (CAP), are increased in patients with depression. Furthermore, administration of inflammatory stimulito laboratory animals and humans causes depressive symptoms, especially reduced motivation or anhedonia, which is one of the core symptoms of depression. Inflammatory stimuli have also been shown to decrease neural activation of brain regions that regulate motivation. Based on the Pl's translational studies in non-human primates, the effects of inflammation on motivation appear to be related to decreased release of dopamine in the ventral striatum. Interestingly, dopamine release can be restored by administration of the dopamine precursor, levodopa (l-DOPA). Our recent data also indicate that the effects of inflammation on dopamine extend beyond the striatum to include other brain regions such as prefrontal cortex. Indeed, increased inflammation has been associated with decreased functional connectivity between the ventral striatum and ventral medial prefrontal cortex that is associated with symptoms of anhedonia. Moreover, pilot data from four patients suggest that these inflammation-related disruptions in corticostriatal connectivity can be reversed by administration of L-DOPA. To further explore the hypothesis that L-DOPA can reverse inflammation-related changes in corticostriatal connectivity and associated anhedonia using a placebo controlled design, the following aims are proposed: Aim 1: To determine if acute administration of L-DOPA can reverse inflammation-related decreases in corticostriatal connectivity. Medically healthy, medication free depressed patients with high inflammation (CAP >3 mg/L; n=10) will undergo resting state fMRI before and after administration of low dose L-DOPA-carbidopa (100/25 mg) and placebo on separate, double blinded visits. Hypothesis 1: Administration of L-DOPA will increase functional connectivity between the striatum and prefrontal cortical regions compared to placebo. Aim 2: To examine whether L-DOPA-mediated increases in corticostriatal connectivity are associated with improvement in objective measures of motivation. Patients described in Aim 1 will undergo performance-based assessments of motivation and self-report assessments of anhedonia, following administration of L-DOPA and placebo, which will be correlated with changes in functional connectivity. Hypothesis 2: L-DOPA administration will be associated with improvement in motivation compared to placebo. These results will be used as preliminary data for a R01 application focused on development of novel therapeutic strategies to reduce inflammation-rel ated symptoms of anhedonia by increasing availability of dopamine precursors.

William R. Hunt, MD
Pulmonary, Allergy & Critical Care Medicine | School of Medicine
Glutathione redox imbalance in CF and CFRD lung disease

Cystic Fibrosis (CF) is a recessive, lethal disease that affects over 74,000 individuals world-wide. It is characterized by functional pulmonary decline that ultimately leads to an untimely death. The most common co-morbidity in CF, affecting more than 50% of the CF population, is the development of CF-related diabetes (CFRD). CFRD further accelerates the pulmonary decline that is already the primary driver of mortality in this disease. It has also been shown that CF patients have profoundly diminished levels of airway glutathione (GSH), a biothiol that is arguably the most important in regulation of airway redox states and oxidative balance. The excessively elevated concentration of airway glucose detected in CFRD may further perturb the oxidative imbalance and exacerbate airway inflammation and infection. This proposal seeks to assess the effectiveness of indirect and direct redox manipulation with GSH supplementation in the region of the CF and CFRD lung that is most affected—the extracellular compartment. Additionally, this proposal will assess the effectiveness of GSH supplementation during pulmonary infection to determine the redox regulation of bacterial clearance.

Heba Iskandar, MD MSCI
Department of Digestive Diseases | School of Medicine
Assessment of health literacy, medication adherence, and a pilot multi-component intervention to improve medication adherence in patients with Inflammatory Bowel Disease

Introduction: Inflammatory Bowel Disease (IBD) currently affects 1.5 million individuals in the United States, with a prevalence of 200 cases per 100,000 individuals. IBD treatment involves a complex medical therapy that requires medication adherence, frequent monitoring, and good patient-provider communication. Previous research has identified that health literacy plays a role in medication adherence; however, there are currently no studies evaluating health literacy in adult IBD patients and no studies evaluating if health literacy relates to medication adherence in IBD. Furthermore, implementation research is needed to establish strategies to improve medication adherence and health related quality of life in IBD. Methods: Our program will address these gaps in knowledge in two ways: 1) Formally assess health literacy and medication adherence in a cohort of IBD patients at the Emory gastroenterology clinic; and 2) Enroll non-adherent patients in a multi-component 24-week targeted intervention aimed to improve the primary outcome of medication adherence, tailored to the individual patient's needs. The study design will be a prospective cohort followed for 24 weeks with a case-crossover component for the intervention. Secondary outcomes such as hospital admissions, surgery rates, disease flares, and changes in health-related quality of life will also be assessed. Anticipated results: We anticipate that low health literacy will be associated with low medication adherence, and that our intervention will lead to improved medication adherence. Significance: This study will be a unique assessment of health literacy in IBD with the addition of a multi-component intervention targeting medication adherence. Our ultimate goal is to improve adherence, health-related quality of life, and disease activity, and target low health literacy earlier in the course of IBD. These findings could greatly improve real-world clinical care for IBD patients.

Jeffrey J. Olson, MD
Neurosurgery | School of Medicine
Molecular Analysis of Vestibular Schwannomas to Access Treatable Targets: Applying Current Technology to a Rare Disease

Vestibular schwannomas (known traditionally as acoustic neuromas) are rare lesions that have a substantial impact on the quality of life of those individuals in whom they develop. Therapy hinges on surgery, radiation or both and is imperfect in that they can induce substantial new and permanent neurologic deficits and still not be curative. Preliminary reports of targeted molecular therapy for these lesions have been reported. We have developed a large bank of surgical specimens over the past years. This proposal will assess the genomic and expression abnormalities (with whole exome sequencing and RNA-Seq techniques, respectively) of these tumors in detail to discover reasonable candidates markers for determining what lesions might be treated with targeted medical therapies. This is the first phase of a three phase plan to approach medical therapy of vestibular schwannomas. The data derived here will provide the substrate for an R21 application to validate this diagnostic panel. Then with this panel in hand, a clinical study guided by this panel will be carried out.

Kehmia Titanji, PhD
Endocrinology | School of Medicine
Reversing HIV-induced B cell dysfunction using Zoledronic Acid

Due in large measure to the success of combination antiretroviral therapy (ART), HIV-infected individuals are living longer than ever before, although life expectancies for HIV-infected individuals remain lower than in the general population. It is estimated that over half of the HIV/AIDS population in the US is now over 50 years of age. This increased longevity is accompanied by increased prevalence and earlier incidence of non-AIDS age-related comorbidities including neurocognitive, renal, hepatic, cardiovascular and skeletal disease. Enduring chronic immune activation that drives inflammation, even in the context of otherwise successful ART contributes significantly to the development of these comorbidities. Preventing and/or mitigating HIV/ART-related comorbidities is increasingly becoming a major challenge in HIV disease management. The overarching goal of this study is to investigate a novel therapeutic approach to ameliorate or reverse B cell dysfunction driving inflammation in patients with HIV infection on chronic ART. HIV infection leads to severe phenotypic and functional impairment of the B cell compartment, which is not effectively reversed by ART and manifests as: (i) expansion of abnormal B cell subsets including immature and pro-inflammatory memory B cells; (ii) hyper-activation characterized by polyclonal B cell activation with increased expression of pro-inflammatory cytokines including IL-6, IFN-γ, TNF-α and RANKL; and (iii) increased autoantibody production (including anti-nuclear antibodies (ANA). These B cell secreted inflammatory cytokines promote a systemic inflammatory environment that is further augmented by autoantibody driven adaptive immune responses that together contribute significantly to multiple end organ damage. Consequently, pharmacological amelioration of these B cell pathologies would be an optimal strategy to alleviate systemic inflammation and downstream end organ damage. The goal of this project is thus to demonstrate the utility of a novel therapeutic agent for reversing B cell dysfunction in human subjects with HIV-infection on ART. Bisphosphonates, such as Zoledronic Acid (ZA) are small-molecule inhibitors of bone resorption and are the mainstay of fracture prevention in osteoporotic conditions. Importantly, studies in bisphosphonate-treated mice unexpectedly found increased generalized antigen (Ag)-specific humoral immune responses, suggesting an enhancement of B cell functions. Bisphosphonates may thus be attractive agents for mitigating B cell dysfunction, attenuating inflammation and ameliorating end-organ complications in HIV-infection. Interestingly, a few studies have demonstrated that BPs are able to significantly decrease the titers of pro-inflammatory markers including C-reactive protein, IL-6, IL-1 and TNF-α, suggesting an effective anti-inflammatory effect of BPs in rheumatoid arthritis. We hypothesize that ZA can ameliorate or reverse HIV-induced B cell dysfunction, and as such the global inflammatory environment that leads to end-organ damage. Moderating and/or reversing this B cell dysfunction will mitigate or prevent organ damage in the aging HIV/AIDS population