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Communicating Research Intent and Value in NIH Applications:
DESCRIPTION: In the US, congestive heart failure (HF) is a common and lethal disease. Approximately 500,000 patients are diagnosed with, and ~300,000 deaths occur, each year due to HF. Over the past half century, several advances in the treatment of patients with HF (e.g. 2-adrenergic receptor blockade therapy) have improved survival, but only modestly. As HF remains the most prominent cause of morbidity and mortality in the US, it follows that current therapeutic techniques are not adequate. Sympathetic overactivity plays a prominent role in disease progression. The long-term goals of the PI are to better understand the mechanisms that regulate the autonomic nervous system excitability in HF, which should lead to novel approaches for treating HF. Over the last several years our research efforts have focused on the roles played by excessive G-protein signaling in contributing to sympathetic over-excitability in HF. G-protein over-activation triggers a biochemical signaling cascade that leads to b-AR desensitization and down-regulation that are characteristic of HF. Our preliminary data indicate that inhibiting G-protein activity restores cardiac function and morphology in an animal model of HF. Interestingly, G-protein signaling has been shown to activate several kinases, including G-protein coupled receptor kinase 2 (GRK2), PI3K, and ERK1/2. Our hypothesis is that excessive G-protein signaling leads to altered protein kinase regulation of sympathetic excitability that expresses as sympathetic overactivity contributing to the development and progression of HF. We will test this hypothesis in the following Specific Aims. Specific Aim #1 of this proposal will test protein kinase activators and inhibitors for their effects on physiological function such as cardiac output, heart rate and arterial blood pressure. We hypothesize that overactivation of GRK2 will augment physiological function. In Specific Aim #2 of this proposal, we will use gene expression methodology to over-express protein kinases to determine their individual contributions to physiological function and morphology. We hypothesize that over-expression of GRK2 will enhance function and alter morphology. For Specific Aim #3, we will use patch clamp techniques to determine changes in cell excitability due to altered kinase activity. We hypothesize that overactive kinase activity produces altered potassium channel activity of sympathetic neurons which contributes to enhanced sympathetic excitability. Completion of these studies will provide an enhanced understanding of the cellular and molecular mechanisms underlying sympathetic neuron dysfunction and the progression to HF. These studies will lay the groundwork for future experiments to identify novel therapeutics to treat this disease.
PUBLIC HEALTH RELEVANCE: Heart failure (HF) is a debilitating disease with poor prognosis. The proposed research aims to investigate the molecular and cellular mechanisms that contribute to the development and progression of HF. Successful completion of experiments outlined in this proposal will enhance our current understanding of an established HF signaling pathway, and may provide a novel therapeutic strategy for the treatment of HF and associated sympatoexcitatory diseases.
CONCEPTS: Consider What to Clearly Communicate to the Public
Example 1: AFTER
DESCRIPTION: Congestive heart failure is a common and lethal disease in the U.S. Current medications for treating heart disease improve survival in some, but not all, patients. Therefore, additional medications are needed to treat individuals who do not respond to current medications. Research using animal models suggests that abnormal G-protein signaling may be a biochemical mechanism that may be one of the factors that cause heart disease. However, it is unknown how altered G-protein activity would cause this disorder. It has been shown that G-proteins can regulate the activities of several protein kinases. It is also thought that protein kinase activity in turn modulates sympathetic nervous system function. As a first step to determine whether this sequence of events could lead to heart disease, this project will use pharmacological and molecular genetic approaches to establish whether a G-protein-regulated protein kinase can modulate cardiac physiology in vivo and cardiac cell activity in vitro. Possible protein kinases to be tested that are regulated by G-proteins include G-protein coupled receptor kinase 2 (GRK2), PI3K, and ERK1/2. This research will enhance our understanding of the cellular and molecular mechanisms underlying sympathetic neuron dysfunction that may progress to heart disease, and may identify a possible novel pharmaceutical target for future experiments to develop therapeutic compounds to treat this disease.
PUBLIC HEALTH RELEVANCE: Heart disease is a leading cause of death in the U.S. Medications currently being used to treat heart disease are helpful to many individuals but do not work on all patients. Therefore, there is a vital need to develop additional drug treatments that will provide multiple approaches for treating all individuals afflicted with this debilitating illness. This research should provide important information that can be used in developing new heart disease therapies.
DESCRIPTION: This application seeks to test a newly-developed HIV prevention program, SafeSex4.0, designed for men who have sex with men (MSM). We propose a randomized trial to test the clinical effectiveness of this integrated intervention approach at the individual, network, and community levels to effect behavioral change. Epidemiological studies have shown that HIV prevalence in large US cities among MSM has declined during the past several years. Correspondingly, HIV prevalence within the MSM population in more suburban areas is on the rise, being shaped by a variety of social and policy forces including population growth and movement of populations to surrounding suburban areas, changes in social norms, and changes in legislation that affects the gay and lesbian communities. At the same time, there has been a sharp decline in the U.S. economy that is making it difficult to maintain, let alone expand, healthcare services for HIV infected individuals. While some community-based services are currently available, there remains a critical need to improve access to care and sustain adherence to treatment plans for HIV-infected individuals within the MSM population. In this study, we propose to further develop SafeSex4.0, pilot a test of the program, and conduct a randomized study of the program at three sites (Salem, OR; Enid, OK; Fredericksburg, VA) across the country. This study has the potential to successfully address a significant public health and healthcare services need. We intend to accomplish these goals through the following. This project has three specific aims. Aim 1 will characterize in-depth the nature of sexual identity, sexual practices, stigma, discrimination, health care access and health-seeking behaviors among MSM. We will use these data to identify sexual risk factors and fine-tune behavioral approaches in improving our prevention program to address the health service needs within the MSM community. Aim 2 will conduct a pilot trial of SafeSex4.0 to further test the feasibility and validity of the program. The results from the pilot test will be used to further refine the program. Aim 3 will evaluate the clinical effectiveness of SafeSex4.0 by conducting a randomized clinical trial. The prevention program will utilize individualized counseling services, support group meetings, and education materials. We will measure the effectiveness of the program in study participants tested positive for HIV and compare findings to a control cohort. We will perform analyses to assess success of the intervention at the network and individual levels. This study will provide support that an improved, carefully-structured prevention program for MSM will lead to greater prevention, diagnosis and care of HIV infection in this group.
PUBLIC HEALTH RELEVANCE: In this study, researchers at three sites across the U.S. will work together to develop and validate an integrated prevention program, SafeSex4.0, to reduce the risk of HIV infection in men who have sex with men (MSM) in suburban communities. This prevention program will offer comprehensive, integrated healthcare services, and will enhance the health of MSM by reducing risky behavior, providing greater access to care and services, and establishing networks of social support. The findings obtained from this study may be used to inform decisions about healthcare policy and implementation of clinically-effective interventions.
CONCEPTS: Consider What to Clearly Communicate to the Public
Example 2: AFTER
DESCRIPTION: Various behavioral health programs have been developed to combat HIV transmission between individuals. Unfortunately, the incidence of HIV infection continues to be problematic within the United States. Clinically-effective prevention programs should continue to be developed to meet the healthcare needs of those at risk of HIV infection. This application will develop a new HIV prevention program, SafeSex4.0, and test the effectiveness of this program with men who have sex with men, a study population who has experienced a significant increase in HIV transmission between individuals. SafeSex4.0 comprises an integrated intervention approach at the individual, network, and community levels to effect behavioral change. The proposed research will accomplish its objectives by first identifying behavioral and healthcare factors within the study population that could lead to increased risk of HIV infection and incorporating interventions against these factors into the design of SafeSex4.0. The program will next be evaluated to test the feasibility of providing the program to the community and to validate the program. Lastly, a randomized trial will be conducted to determine the clinical effectiveness of the program. The availability of additional community-based HIV prevention programs will provide alternate healthcare intervention and treatment options for reducing and preventing HIV transmission between individuals.
PUBLIC HEALTH RELEVANCE: Anti-retroviral drug therapies and behavioral intervention programs have been effective for treating and reducing HIV infection. Yet although overall infection rates have declined, HIV infection rates for some populations in the US continue to rise. Therefore, it is important to develop additional clinically-proven prevention programs, such as the one studied in this project to fully reduce the incidence and prevalence of HIV infection across the US.
DESCRIPTION: Usage of alcohol and other drugs of abuse is rapidly rising in Nigeria. Since 2000, self-reported use of alcohol has increased by 25%, the use of tobacco by 37%, and of heroin by 47%. These increases in substance use pose a significant threat to the public health and safety in this resource-limited nation, where programs and funding for healthcare services in general, but especially for the treatment of substance abuse and addiction, are largely unavailable or sporadically provided. The purpose of this international research project is to conduct a collaborative study to define both risk and protective factors for, and the prevalence of, alcohol, tobacco and heroin use in a nationally-representative sample of Nigerian truck drivers between the ages of 12-25 years old. This group has experienced the largest increase in the use of these three drugs for the past five years. We propose to employ both qualitative and quantitative research methods to determine the roles of social, behavioral, and environmental indicators on drug use. The specific objectives of this proposed research are: 1. To determine the prevalence of alcohol, tobacco and heroin use and abuse among truck drivers. 2. To examine the associations between drug use behaviors and environmental and social factors and 3. To assess the behaviors and belief systems of drug users as related to the use individually or in tandem of these three drugs. Specific Aims 1 and 2 will be achieved by combining in-depth national surveys on drug use with hospital emergency room reported health data on truck drivers treated for alcohol, tobacco and heroin related disorders. These aims will provide information on the etiology of drug use among this population. Specific Aim 3 will be achieved by conducting in-depth qualitative interviews and focus group evaluations on a selected sub-sample at truck stops across Nigeria to discern further details of their alcohol, tobacco and heroin use behaviors, and on other aspects of their use including risk and protective factors. The long-term goal of this study is to determine behavioral, social, and environmental factors predictive of drug abuse to inform future interventions to reduce hazardous drug use.
PUBLIC HEALTH RELEVANCE: We propose to conduct a collaborative, mixed methods study on alcohol, tobacco and heroin abuse and addiction in Nigeria. This is a country where substance abuse has been increasing recently, and where limited resources and treatment programs exist for substance abuse and addiction. Both qualitative and quantitative survey methods truck drivers will be administered to gain insights on the prevalence and the risk and protective factors of alcohol, tobacco and heroin use. Such information is needed for future prevention and intervention efforts, and may be applicable to wider medical settings such as primary healthcare in other resource-poor communities throughout the world.
CONCEPTS: Consider What to Clearly Communicate to the Public
Example 3: AFTER
DESCRIPTION: The abuse of alcohol, tobacco and heroin has significant medical, behavioral and social consequences on individuals and society in the United States. In addition, healthcare costs for the treatment of substance abuse and addiction continue to rise. Therefore, methods need to be developed that decrease the incidence and prevalence of substance abuse while also controlling and reducing the costs of its treatment. Effective, low-cost treatment programs should speak to the motives that compel individuals to use drugs. The objective of the proposed research is to identify social, behavioral, and environmental factors that influence the use of alcohol, tobacco or heroin. These factors will be determined from surveying a study population, truck drivers in Nigeria, whose drug usage is rising. A unique aspect of the study sample is that these individuals also have limited access to resources for the treatment of substance addiction. Therefore, their drug use behaviors and beliefs may be useful in developing low cost approaches for the treatment of substance use disorders in other parts of the world, including the US. To complete its objectives, this research project will analyze data collected from national surveys and hospital emergency room health statistics to determine the prevalence of alcohol, tobacco and heroin use, and to identify environmental and social factors that promote drug use. Additionally, this project will conduct in-depth qualitative interviews and focus group evaluations to correlate personal attitudes and beliefs with drug use. This project should identify risk and protective factors that can be incorporated in the future design of low-cost behavioral interventions to reduce drug use.
PUBLIC HEALTH RELEVANCE: Substance abuse and addiction places a significant burden on individuals, families and society in the United States. The healthcare costs for treating substance addiction can be staggering. This research will contribute to the development of clinically-effective methods for reducing substance use that are provided at low or minimal cost, which will be of medical and economic benefit to all.