2002 — 2005 |
Philibert, Robert A |
K08Activity Code Description: To provide the opportunity for promising medical scientists with demonstrated aptitude to develop into independent investigators, or for faculty members to pursue research aspects of categorical areas applicable to the awarding unit, and aid in filling the academic faculty gap in these shortage areas within health profession's institutions of the country. |
A Thyroid Receptor Co-Activator Hypothesis For Psychosis
DESCRIPTION: (provided by applicant) Schizophrenia is a neurodevelopmental syndrome that affects approximately 1 percent of the U.S. population and is characterized by the presence of hallucinations and delusions. Genetic factors are thought to account for the majority of the vulnerability to illness for this syndrome. These genetic factors are thought to be composed of major, moderate ant mild effect loci. The identification and characterization of genetic factors of even mild effect loci is a critical step in the process of understanding the pathogenesis of this group of disorders. In prior moleular studies, the candidate has identified an exonic polymorphism (HOPA12bP) in a critical portion of a gene for a thyroid receptor co-activator named HOPAthat is associated with a behavioral endophenotype that include schizophrenia and hypothyroidism. In this five year training grant, the candidate proposes to focus on the behavioral syndrome that is associated with the polymorphism and 1) demonstrate segregation of the polymorphism with illness. 2 refine the phenotype associated with the polymorphism, and 3) identify other mutations that may be related to illness. Scientific Aims of this grant are 1). Peform case control analyses on schizophrenic probands with the HOPA12bp polymorphism. Schizophrenic HOPA probands will be identified and compared to matched case controls for cognitive/behavioral, endocrinological and medical differences. 2. Conduct a focused linkage study of the families of HOPA12bp probands. Structured interviews will be used to assess the presence of cognitive/behavioral and medical co-morbidity in the first-degree relatives of control and HOPA12bP probands. These results will be correlated with genetic status. 3). Conduct SSCP analysis across the HOPA Gene to detect other potentially pathogenic mutations. Mutation analysis will be performed using DNA from other schizophrenic patients to detect other mutations in theHOPA gene that can result in result in this syndrome or related phenotypes. Training Aims of this grant are to 1) develop clinical skills in the diagnosis and standardized measurement of complex behavior and endocrinological disorders, and 2) learn medical and psychiatric epidemiology, ethics, and biostatistical approaches to complex disorders. The net effect will be to produce an independent investigator capable of functional and translational research.
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0.958 |
2004 — 2008 |
Philibert, Robert A |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Genetic Studies of Substance Abuse in Iowa Adoptees
[unreadable] DESCRIPTION (provided by applicant): The purpose of this revised grant application is to solicit funding to add a molecular genetic component to the extensive epidemiologic data on Substance Use Disorders (SUD) available in the Iowa Adoption Studies. These epidemiologic studies include over 900 adult adoptees, separated at birth from biologic parents, interviewed over a 20 year period, who are now being re-interviewed with a focus upon lifetime substance use/abuse/dependency. Over the past two decades in studies of these adoptees, our research group has shown significant genetic and environmental effects and gene-environment interactions that affect both early life risk factors for substance abuse and the course of adult substance use/abuse/dependency. The adoption paradigm has furthered the study of the development of risk behaviors for SUD by allowing the examination of how genetic factors may interact with environmental factors such as parenting behaviors in the adoptive home and is the study design of choice for the detection of these important gene environment interactions. In this application, we hypothesize that genetic variability and certain gene environment interactions are responsible for increased vulnerability to SUD, and in particular, Nicotine, Alcohol and Marijuana abuse/dependence. To test this hypothesis we will: 1) Conduct follow-up behavioral and cognitive assessments (including quantitative measures of SUD risk), then collect DNA samples from the our well characterized cohort of adoptees 2) conduct candidate and single nucleotide polymorphism analysis with respect to the best validated candidate genes or loci, and 3) analyze the resulting data using association and multifactorial regression to create a testable model of single gene, gene* gene, environmental and gene*environment contributions to the susceptibility to SUD. As direct result of these experiments, we will determine specific gene and gene-environment interactions that contribute to increased vulnerability to SUD. The identification of these interactions, and in particular gene x environment interactions, is important as it will allow the development of more effective biological and environmental (e.g. changing parenting behaviors or the formulation of new behavioral treatment strategies) interventions for the treatment of SUD. As an indirect result of these experiments, the scientific community will gain a unique and valuable genetic resource that can be utilized by other investigators of genetic and epidemiologic vulnerability to SUD in showing that these Iowa Adoption Studies through the NIDA Genetics Consortium. [unreadable] [unreadable]
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0.958 |
2008 — 2012 |
Philibert, Robert A |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Examination of Genetic and Gxe Effects in the Family and Community Health Studies
[unreadable] DESCRIPTION (provided by applicant): The purpose of this grant application is to integrate a molecular genetics component to a currently funded study of the effects of behavioral and environmental factors on psychological well-being and diagnostic status of African-American (AA) subjects participating in the Family and Community Health Study (FACHS). The biomaterial for the proposed project will be collected from an existing sample of 771 African American families from Iowa and Georgia who were recruited to participate in the Family and Community Health Study (FACHS), all of whom had a child who was 10 to 11 years of age at the time of recruitment into the study in 1997. The data we have already collected from these women and their families provides a rich and extensive longitudinal foundation upon which to build the proposed project. The proposed use of previously validated genetic markers in addition to sensitive measures of context reduces error variance and capitalization on chance, setting the stage for well targeted analyses that extend theoretical models in important new directions. The FACHS sample is particularly valuable because a large body of evidence has accumulated that demonstrates that both genetic (G), gene-environment correlations (rGE) and gene-environment (GxE) interactions are important in influencing vulnerability to a wide variety health-related outcomes including obesity, hypertension and depression. To date, however, these studies have largely focused on populations of northern European ethnicity to the exclusion of other ethnic groups. In addition, the current sample provides an opportunity to examine previously unrecognized resilience factors in the AA population. We propose to identify specific risk and resilience factors for depression and substance. We hypothesize that G, rGE, and GxE interactions comprise a portion of the risk and resiliency factors responsible for altering vulnerability to depression and substance use in these women. To test this hypothesis we will: 1) collect DNA samples from 1076 subjects (primary and secondary care givers with approximately 200 of the secondary care givers being marital partners), 2) conduct genotyping studies of the best validated candidate genes or loci, 3) conduct analyses of the resulting data to identify factors conveying risk or resilience to depression or substance use, and 4) then examine these factors in the context of longitudinal, contextually sensitive, developmental models of depression and substance use. As a direct result of these studies, we will determine specific G, rGE and GxE effects that either confer protection or confer increased risk for depression, substance use and other health related outcomes among AA women. PUBLIC HEALTH RELEVANCE: The purpose of this grant application is to add a molecular genetics component to a currently funded study of the effects of behavioral and environmental factors on psychological well-being and diagnostic status of African-American (AA) subjects participating in the Family and Community Health Study (FACHS). [unreadable] [unreadable] [unreadable]
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0.958 |
2012 — 2013 |
Philibert, Robert A |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
The Effects of Smoking On Dna Methylation in Primary Human Lymphocytes.
DESCRIPTION (provided by applicant): Smoking is a behavior that results from a complex developmental interplay of genetic and environmental processes. Smoking, in turn, causes a number of adverse health outcomes. Using other tissue preparations, we and others have shown that some of these adverse effects of smoking may be mediated by altered DNA methylation. However, whether smoking induces differential DNA methylation in lymphocytes is still highly controversial and whether any observed differential methylation is functionally relevant is completely unknown. In this R21 application, we propose to unequivocally determine whether smoking is associated with changes in lymphocyte DNA methylation and set the stage for future investigations by ourselves and others. To accomplish this goal, we will use the bioresources of two large, informative, ethnically diverse populations. The first population, the Iowa Adoption Studies (IAS) is the largest case and control adoption study in the United States. The IAS has been pivotal in the demonstration of the importance of genetic (G), environmental (E) factors and gene-environment (GxE) interactions in the development and maintenance of common behavioral illnesses including major depression and nicotine dependence. The second population, the Family and Community Health Studies (FACHS), is a large longitudinal study of the impact of sociopsychological factors such as racism and poverty on depression and health behaviors in 900 rural African-American families. The over-arching hypotheses of our research group are that substance use is associated with epigenetic changes and that some of these changes may be important in both moderating the continuation of substance use and the vulnerability to smoking related comorbidities. Unfortunately, to date, many in the field do not believe that smoking, or any other form of substance use, leads to alterations in peripheral lymphocyte methylation. To set the groundwork for integrated studies of the role of epigenetic factors in smoking, we will test the hypothesis that smoking is associated with changes in DNA methylation. To do this, we will use our established approaches to identify genomic regions whose methylation is altered in smoking using primary lymphocyte DNA from female IAS and 800 FACHS subjects. Because our populations are well characterized for behavioral and physical outcomes, we have complete sets of biomaterials and data for future studies and are embedded transdisciplinary collaboration, we are well poised to rapidly exploit any positive findings. This application is innovative because the effect of smoking on lymphocyte DNA methylation is highly controversial and has not been unequivocally demonstrated. Since lymphocytes are key players in smoking associated autoimmune illnesses and may be effective proxies for CNS epigenetic processes, the successful demonstration of effects of smoking on DNA methylation will have an impact on health care because these investigations of this critical cell type may lead to new interventional strategies for smoking and smoking related comorbidities. It is highly feasible because it builds off existing populations and repositories. Finally, the investigative team is well prepared and includes a molecular biologist/psychiatrist with extensive experience in methylation studies and a well-trained bioinformatician.
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0.958 |
2014 — 2017 |
Gerrard, Meg (co-PI) [⬀] Philibert, Robert A |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
The Relationship of Ahrr Methylation to Risky Adolescent Behaviors
DESCRIPTION (provided by applicant): Smoking is the most common preventable cause of morbidity and mortality in the United States. In efforts to block the initiation of adolescent smoking, a variety of public health measures have been implemented. Despite the success of these measures, a substantial minority of all adolescents still begin the initial 1- 3 year period f experimentation that can lead to regular daily smoking. Effective interventions to block the escalation of this initial smoking exist. However, the implementation and effectiveness of these interventions is hindered by 1) an inability of pediatricians and allied health professionals to detect the presence of the periodic use of cigarettes that characterizes this phase and 2) an inexact understanding of smoking initiation to co-morbid features such as risky sex and alcohol use. This failure deprives a substantial number of adolescents of an opportunity to stop the escalation of smoking and smoking related behaviors during a critical phase of development and education. Recently, we have shown that DNA methylation at AHRR may be a sensitive indicator of early onset adolescent smoking. However, our studies are incomplete in that we have not fully characterized the smoking dose response curve, the effect of other environmental influences, such as second hand smoke, on DNA methylation, and the relationship of DNA methylation to existing indicators of smoking status. In this R01 application, we propose to improve our ability to detect and comprehend the trajectory of smoking behaviors by serially examining a large longitudinal cohort of 450 adolescents at risk for smoking and their families over a two year period. We will determine DNA methylation, serum cotinine and exhaled carbon monoxide levels at multiple time points and exhaustively characterize their environments for potential confounding factors. We will analyze the resulting data with respect to the clinical variables to determine the relationship of DNA methylation to smoking related variables. This application could have high clinical impact, because it may identify a sensitive biomarker of nascent smoking in a population at high risk for complications from smoking and provide a research tool that may allow a wide range of researchers to revisit large existing data sets that focus on youth to investigate health effects of smoking exposure. It is highly feasible because our investigative team has a long history of conducting this type of longitudinal study and we are the discoverers of this biomarker of smoke exposure. It is innovative because unequivocally demonstrated sensitive biomarkers for nascent smoking do not yet exist. The investigative team is led by a well-established physician-scientist and two behavioral interventionists with experience in methylation studies. As a result of this research, we will establish the relationship of AHRR methylation to smoking consumption variables, other biomarker status and environmental exposures (e.g. second hand smoke) that can be used by other for clinical interventions and as a biomarker of smoking exposure for existing DNA collections from epidemiological studies.
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0.958 |
2018 — 2021 |
Beach, Steven R Gibbons, Frederick X [⬀] Philibert, Robert A |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Contextual and Health Behavior Effects On Epigenetic Aging Among African Americans @ University of Connecticut Storrs
ABSTRACT: Considerable evidence exists linking early stress to accelerated aging, but potential mechanisms (mediators) accounting for this effect are poorly understood. Likewise, the impact of continuing stress in young adulthood on accelerated aging is largely unknown. Compounding the lack of information regarding mechanisms and timing of effects, available research is limited because it has focused mostly on White samples -- in spite of the fact that Blacks have significantly higher rates than other racial/ethnic groups of almost every type of chronic illness, as well as most markers of inflammation, and epigenetic aging (epi-A) ?i.e., the difference between chronological age, and biological age, based on epigenetic changes in DNA methylation. The proposed research is designed to examine: a) factors that affect accelerated aging in Blacks, especially economic and race- related stress; and b) the role of mediators and moderators that may be useful targets for preventive interventions, such as substance use and poor diet, and also protective factors. A focus of the current investigation is testing alternative pathways to accelerated aging attributable to early and later stressors. One pathway focuses on stressor effects on potentially unhealthy behavior (e.g., substance use, diet) that may, in turn, give rise to chronic diseases of aging. This possibility is supported by evidence that stressful life events, especially those linked to discrimination, predict life style choices. Conversely, stress effects may also accelerate aging by altering functioning of the glucocorticoid system. Or, the two pathways may be interrelated. In addition, we focus on expanding what is known about the range of stressors within a given developmental period that are most critical, and the extent to which protective factors affect epi-A. Addressing an important limitation of prior research, we will have reliable, sensitive biomarkers of smoking, marijuana, alcohol use, and diet available at two time points as well as census track and parent report indices of stressors at multiple time points, allowing and us to supplement self-report measures and examine models more rigorously and with greater precision than has previously been possible. The proposed research will focus on 470 young adults who are part of a larger (N=889) panel study of Black families, the Family and Community Health Study. FACHS has followed a cohort of ?target? participants from ages 10 to 28, along with their parents and family members. By characterizing methylation using the Illumina Epic array for two time points in young adulthood (28 and 33), we will be able to determine change in epi-A; i.e., the extent to which accelerated aging continues to be malleable in young adulthood. Using existing self- and parental reports of a variety of stressors-- from 8 waves of data, along with well-validated epigenetic biomarkers of epi-A, smoking, and drinking, we will be able to leverage the exceedingly rich existing prospective FACHS dataset, including its information on stress, protective factors, substance use, and coping, with the goal of informing preventive intervention research that can address the sources of disparities in healthy aging.
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0.934 |