Robert Paul - US grants

This project will develop a curriculum of philosophical studies, with an emphasis on ethics, especially appropriate for graduate students in the sciences. The curricular model will be implemented in the specific setting of a marine biological laboratory. In many respects such laboratories resemble small, liberal arts college campuses. The setting should be conducive to integrating philosophical and scientific issues, methods, and problems. Four course modules or seminars are proposed in the following order: 1) Theories of Sciences; 2) Theories of Ethics; 3) Ethics of the Environment and Development; and 4) Professional Ethics. Each are two-credit, half-semester courses, which will meet for two hours a week over eight weeks; students are expected to participate in the entire sequence. Novel features include introducing graduate students to philosophy through a course in the history and philoosphy of science, requiring work in ethical theory before truning to issues in applied ethics, including non- Western (Chinese) materials and perspectives in all facets of the curriculum, and exploring the question of need or desirability of developing a specific code of professional ethics for research scholars in the biological and envirnomental sciences. Results from the project will be disseminated at the meetings of two scientific groups: The National Association of Marine Laboratories and The Estuarine Research Federation. There are also plans to develop a syllabus and annotated bibliography.

Many undergraduate programs in mathematics and science do not adequately emphasize the central role played by mathematics in the investigation of problems that originate in biology and chemistry. The central role that mathematics plays in the advancement of all branches of science has created the demand for biologists and chemists who are quantitatively literate, mathematicians who can work with scientists in collaborative problem solving efforts, and educators who have a broad perspective on the interplay between mathematics and the sciences. This project is developing a library of modules through which students majoring in biology, chemistry, mathematics, and mathematics education will gain substantial practical experience in the application of mathematical methods to biology and chemistry. Each module will be developed through a collaborative effort by mathematics and science faculty and will address individual applications at four levels -- precalculus, differential calculus, integral calculus, and differential equations. At each level, different aspects of the application will be explored depending on the mathematical tools available at that level. Through use of the modules in mathematics courses and science laboratory courses, science and mathematics students will learn to work together as a problem solving team and to accurately express the results of their mathematical and scientific investigations in writing. The modules to be developed will be made available in hypertext and printed forms and will be disseminated via the World Wide Web. Faculty workshops on the use of the modules will be held at appropriate national meetings and working relationships with faculty who adopt the modules for use in their courses will be cultivated.

[unreadable] DESCRIPTION (provided by applicant): The purpose of the present study is to investigate CNS injury among injection drug abusers co-infected with HIV and Hepatitis C (HCV). The study will incorporate btomarkers of hepatic disease, state-of-the-art neuroimaging methods, and neuropsychological outcomes. Recent preliminary studies, including data from our lab, indicate that HIV-HCV co-infection is associated with greater neurocognitive compromise than either disease alone. Studies conducted to date have not fully determined the mechanisms underlying the potentially synergistic effect of co-infection. Further, the neurofunctional underpinnings of these effects have not been identified using functional or structural neuroimaging. Recent data from our laboratory identified strong relationships between markers of hepatic disease and cognitive outcome as well as relationships between neuroimaging abnormalities and cognitive function in co-infected individuals. The present study will extend these pilot data and examine CNS abnormalities in co-infected individuals using laboratory, neuroimaging and neurocognitive data. To accomplish these goals we will recruit two groups of active injection drug abusers including: 1) 30 HIV mono-infected patients, and 2) 30 HIV-HCV co-infected patients. All individuals will undergo laboratory testing including assessment of hepatic disease and HIV disease in the periphery, functional MRI, structural neuroimaging and neurocognitive assessment. This cross-sectional association study will be the first transdiciplinary approach to HIV-HCV co-infection, and will provide important insight into the putative mechanisms underlying increased cognitive impairment in this population. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): The purpose of the present study is to investigate relationships between novel neuroimaging markers based on DTI fiber tracking models, genetic polymorphisms of vascular disease and inflammation, and age-related cognitive decline in healthy individuals. Recent studies, including data from our lab, indicate that the integrity of the subcortical white matter as measured by diffusion tensor imaging (DTI) and subcortical hyperintensities on structural MRI are important correlates of age-related cognitive differences. Cortical brain volume changes also account for some variance in cognitive function among the elderly, however our data suggest that alterations in the subcortical white matter more strongly correlate with cognitive status. In addition, studies have demonstrated that white matter alterations in the elderly are heritable, implicating the role of genetic factors in the development of mild ischemic changes and associated inflammation. In this revised application we provide compelling new pilot data demonstrating the role of genetic polymorphisms for vascular injury on both imaging and cognitive indices. We also provide new data from our recent work demonstrating the sensitivity of our novel DTI metrics based on quantified fiber tracking models to explain variance in cognitive aging. These novel metrics allow us to examine the impact of changes in quantified fiber lengths on cognitive function. In the present study we will extend these preliminary studies and examine relationships between DTI and structural MRI, genetic polymorphisms associated with microvascular disease (angiotensinogen, paroxonase) and related CMS inflammation (C-reactive protein, IL- 6, TNF-a), and cognitive status in the healthy elderly. The study will capitalize on an existing database containing genetic and neurocognitive data on more than 1,000 individuals stratified in five groups from age 31-80 (n = 200/group). Neuroimaging data is currently available for 200 of these individuals and we will recruit an additional 120 individuals between the ages of 51-80 to supplement the older age spectrum and obtain novel fiber tracking maps from the DTI data. Newly recruited individuals will be followed longitudinally to examine the evolution and progression of white matter and cognitive abnormalities in the context of genetic risk factors. Group comparisons and latent variable modeling will be conducted to examine relationships between the neuroimaging indices, genetic polymorphisms, and differences in cognitive function in older healthy adults. The present study will be the first to integrate these approaches to examine a model of age-related cognitive decline implicating the subcortical white matter. The results will significantly inform our understanding of cognitive aging. [unreadable] [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The proposed study will capitalize on existing relationships between the University of Missouri, St. Louis, and the University of Cape Town, South Africa to characterize the neurobehavioral signatures of HIV in South African individuals infected with clade C virus. Clade C represents the most common form of HIV in the world and it remains a dominant strain in South Africa. Early studies suggested that individuals infected with clade C HIV may be less likely to develop cognitive impairments due to a natural variation in the dicysteine motif of the Tat protein (C31S) evident in clade C virus. In support of this hypothesis a recent study of individuals infected with clade C virus in Ethiopia exhibited minimal cognitive impairment. However, other biological studies suggest that clade C may infer neurovirulence and we have demonstrated that patients with clade C virus in India exhibit cognitive impairment relative to seronegative controls. Recently we have collected data from a small group of individuals infected with clade C in South Africa, and we also have obtained neuroimaging on HIV patients in South Africa. These preliminary studies suggest that cognition is likely negatively affected in clade C patients residing in South Africa. However, it is unknown whether the cognitive impairments identified in clade C are present in the context of the Tat protein defect, or whether they relate to other known virologic correlates of cognitive function such as proviral DNA level. Further, no study has addressed the neuroimaging signatures of clade C HIV. In the present study we will examine 200 treatment-naive, HIV-positive individuals with clade C HIV and 50 seronegative healthy controls matched on demographic characteristics and all recruited from South Africa. Laboratory, cognitive, and neuroimaging data will be obtained from the patients and controls. Neuroimaging will consist of diffusion tensor imaging (DTI) to derive novel metrics of quantified tractography developed by members of our team (Laidlaw) as well as traditional volumetric indices that are known neuriomaging signatures of impairment in clade B HIV. This will be the first transdisciplinary study of clade C neuropathogenesis and the results will significantly advance our understanding of viral clade diversity and cognitive outcomes associated with HIV. PUBLIC HEALTH RELEVANCE: The purpose of this study is to determine the impact of clade C HIV on cognitive function among individuals in South Africa. We aim to demonstrate that cognitive impairment is present among individuals infected with clade C despite the presence a Tat protein defect. We also aim to demonstrate that these impairments correlate with proviral DNA levels and markers of novel neuroimaging signatures.

ABSTRACT The agrarian political regime of the Khmer Rouge in Cambodia led to the death of nearly 2 million civilians and residual symptoms of distress among many survivors. Recent estimates indicate that nearly 50% of the general population exhibits clinically significant symptoms of trauma-related anxiety and/or depression. Targeting of academic leaders during the genocide further undermined an already vulnerable academic health system needed to support innovations in mental health research and care. Cambodian leadership is committed to resolving the existing mental health gap through strategic partnerships, enhanced capacity building, and adoption of evidence-based treatments (EBT) capable of shifting the trajectory of health and wellness of the population. This application follows on the heels of a successful Phase I program culminating in a clear vision of capacity building needs and national research priorities with high potential for local adoption, scale-up, and sustainability. The proposed application will enrich outcomes from the first phase through completion of three layered and integrated aims. Specific Aim 1 will strengthen the mental health research capacity across performance sites utilizing a combination of standardized content for global mental health and professional development programs tailored for research in Cambodia. Measurable outcomes will support the conceptualization, implementation, and evaluation of externally funded research projects resulting in high impact scientific publications. Specific Aim 2 will examine the acceptability and feasibility of trauma-informed care as a culturally relevant response to trauma exposure. Newly trained and certified research teams led by Cambodian investigators will employ a mixed methods design to evaluate the Missouri Model of trauma-informed care. Specific Aim 3 will determine the effectiveness of a culturally-informed, EBT to reduce symptoms of trauma- related anxiety, depression, and problematic substance use. Preliminary work suggests that the Common Elements Treatment Approach (CETA), a task-sharing EBT has high potential to improve affective disorders and substance use disorders in resource restricted environments. However, studies have only examined CETA administered with ongoing supervision by US-based clinicians. Scale-up and sustainability of CETA in resource restricted environments requires empirical evidence that CETA is effective when administered by providers working in the local health system without ongoing case supervision by international partners. Specific Aim 3 will address this critical issue by comparing CETA modified for independent implementation (mCETA) to standard CETA (sCETA) and waitlist controls. Professional gains obtained from the structured training opportunities will be engaged to complete the clinical trial. Collectively, the structured implementation of this Phase II application will establish a formidable culture of research innovation to address current and future mental health needs of the Cambodian population. Outcomes will inform treatment strategies in other trauma-intense, resource restricted regions of the world.

ABSTRACT This study addresses a critical gap in the field of HIV neuropathogenesis. Previous investigations of brain integrity during the earliest stages of infection describe two opposing neuroimaging signatures of disease. The inconsistency likely reflects the challenges inherent in conducting this work in the US given the limited access to treatment-naïve individuals in early disease stages (Fiebig I-V). Leveraging a highly unique cohort of acutely infected individuals (AHI) in Thailand, our preliminary data reveals intact brain structure and function in treatment- naïve individuals infected for less than two weeks. However, after two years of suppressive combination antiretroviral therapy (cART) initiated within weeks of infection, neuroimaging abnormalities develop in the context of suppressive cART. Further, the degree of brain impairment corresponds to increased levels of monocytes expressing receptors involved in CNS migration and CSF levels of neuronal dysfunction. In this study we will answer the critical question of whether cART is sufficient to halt the detrimental impact of HIV on the brain when initiated within weeks of infection, or whether the brain abnormalities observed in our preliminary analyses progress beyond expectations for HIV- controls despite otherwise successful treatment. This study will overcome limitations in the existing literature because all participants in this study will start cART within days of viral exposure. This work is timely and builds on funded studies that will substantially leverage costs of data acquisition. We will examine longitudinal multimodal imaging outcomes (resting state fMRI, diffusion tensor imaging, and structural volumetrics) of AHI (n=60) as well as enrollment and data capture from demographically-similar individuals with chronic HIV infection (CHI; n=40) and HIV- controls (n=40). A mixed model design will determine if individuals with AHI develop brain injury similar to CHI despite suppressive cART and identify key mechanistic predictors to the evolution of brain abnormalities. Confirmation of our preliminary data demonstrating progressive brain abnormalities despite initiation of cART during the earliest possible period of infection would provide a strong argument that treatment administered under ideal clinical circumstances does not prevent the onset of brain abnormalities. Additionally, evidence of persistent neural injury despite cART instituted during AHI would identify key mechanisms of HIV neuropathogenesis and potential high-impact targets for clinical interventions.

PROJECT SUMMARY-ABSTRACT The purpose of the proposed study is conduct a controlled investigation of HIV host and viral dynamics on brain integrity in vertically infected children on stable combined antiretroviral therapy (cART) in Myanmar. Outcomes from the PREDICT trial in Southeast Asia revealed residual cognitive impairment among pediatric HIV+ individuals with vertical infection. Socioeconomic variables predicted cognitive test performance among infected children and children exposed to HIV but uninfected with the virus. Efforts to define the neuropathogenesis of HIV require adequate control of these environmental variables known to influence cognitive test performance and engagement in ADLs. The majority of HIV+ children in Myanmar reside in privately funded orphanages with standardized caregiver status, nutrition, and education. Our preliminary work reveals cognitive impairment in these children on cART with high CD4 count when compared to demographically matched healthy controls (HIV-). Further, 40% of the HIV+ children express preferential use of the CXCR4 co-receptor and the degree of cognitive impairment is greater among these children compared to those expressing the CCR5 co-receptor despite similar CD4 counts. Previous studies have associated CXCR4 utilization with worse cognition in HIV+ adults with advanced disease, but it is unclear from these studies if co-receptor subtype is liked to cognitive impairment or more simply a correlated variable between disease severity and cognitive impairment. Our preliminary data suggests a mechanistic role for CXCR4 on reduced brain integrity independent of advanced disease, emphasizing the need to identify the relevant immunological factors. Work from our team previously demonstrated that circulating monocyte HIV content, monocyte subpopulations, and myeloid-derived immunological mediators are key mechanisms of HIV-associated neurocognitive impairment. The present study will examine these immunological mechanisms and co-receptor tropism in the cascade of events related to cognitive impairment in vertically infected youth. This information is critical to facilitate the development of targeted treatments to improve cognitive function among children with vertically infected HIV. We will enroll 120 HIV+ vertically infected children and adolescents between the ages of 8 and 15 and 60 HIV- controls matched for demographics, and all residing in privately funded orphanages. Neuropsychological, virological, and immunological assays will be completed to determine pediatric HIV neuropathogenesis in the context of stable cART.

Mental health disorders including depression and neurocognitive impairment (NCI) are the most common central nervous system (CNS) complications of HIV infection despite effective antiretroviral therapy (ART). It is estimated that 40-50% of HIV+ individuals have at least one mental health disorder. Uganda, a low-income country in Sub- Saharan Africa (SSA) has ~1.5 million people living with HIV (PLWH) many of whom are on ART. Despite ART use, CNS complications, which are notably heterogeneous, persist among PLWH. Uganda provides a unique setting for advancing our understanding of major depressive disorder [MDD] and NCI, because common confounding conditions in the United States such as cerebrovascular disease risk factors and illicit drug use (e.g., narcotics, cocaine) are rare in Uganda. We propose to address the overarching hypothesis that there is substantial heterogeneity in MDD and NCI in PLWH and that psychosocial determinants (e.g., sexual and physical trauma, violence) are likely contributors to this heterogeneity. Addressing the heterogeneity in MDD and NCI is critical to advancing our understanding of cognitive phenotypes. To accomplish our aims, we will use a novel methodology for mental health in HIV research, the NIMH Research Domain Criteria (RDoC) framework, which recognizes heterogeneity, to first examine behavioral phenotypes among PLWH followed by studies to understand the functional consequences of these phenotypes and the underlying pathophysiology in these phenotypes. Our study results should lead to more accurate diagnosis, prognosis, and targeted interventions for MDD and NCI in HIV infection globally. We plan to cost-effectively leverage the established infrastructure and data from our previous Rakai Neurology Cohort Study to examine the following aims: Aim 1: Examine separate and interactive effects of HIV and psychosocial determinants on CNS dysfunction in PLWH. Hyp 1. Exposure to sexual/physical trauma or violence will interact with HIV in this population and will be associated with greater impairments/decline in declarative memory, cognitive control, and NVS. Aim 2: Examine effects of psychosocial determinants and CNS dysfunction on ART adherence in PLWH. Hyp 2. Exposure to sexual/physical trauma or violence and/or impairments/decline in declarative memory, cognitive control, and NVS will adversely affect ART adherence. Exploratory Aim 3: Determine biomarkers that relate most strongly and reliably to CNS dysfunction in the context of HIV and/or psychosocial determinants. Hyp 3: Different biomarkers of neuronal damage and CNS inflammation will relate to patterns of impairment/decline in declarative memory, cognitive control, motor, and NVS in the context of HIV and/or exposure to sexual/physical trauma or violence. We will also build capacity to evaluate and conduct research in mental health disorders and introduce new measures of adherence to our cohort. Our proposal addresses several high priority research topics for the NIH Office of AIDS Research including HIV-associated comorbidities, basic research to understand the pathogenesis of mental health disorders in HIV infection, and research to identify viral reservoirs that could lead to a cure for HIV infection.