1998 — 2002 |
Wadhwa, Pathik D |
R29Activity Code Description: Undocumented code - click on the grant title for more information. |
Physiological Stress Reactivity and Pregnancy Outcomes
DESCRIPTION: There is growing recognition that women who experience psychological and social adversity during pregnancy (i.e., prenatal stress) are at increased risk for preterm delivery, even after adjusting for the effects of established biomedical and sociodemographic factors. Studies have examined features of stressors or sociodemographic characteristics to identify factors associated with increased vulnerability to stress; however, with one exception, none of these has examined individual differences in women's biological response to stress. The objective of this proposal is to examine the role of maternal biological stress reactivity in outcomes related to the length of gestation. A prospective study will be conducted in sample of at least 200 women to assess the responses of the sympathetic-medullary-adrenal axis (i.e., blood pressure, heart rate) and hypothalamic-pituitary-adrenal system (i.e., ACTH, cortisol levels) to a standard laboratory-based behavioral stress paradigm at three time-points during gestation (10 to 12, 20 to 22, and 30 to 32 wks). The primary study hypothesis is that greater maternal biological reactivity to stress will predict earlier delivery. Secondary hypotheses include: the effects of maternal biological stress reactivity will be mediated by placental CRH; the magnitude of the biological stress response will decrease with advancing gestational age; and baseline hormonal levels, obstetric risk status, and maternal psychosocial factors will correlate significantly with measures of stress reactivity. Significance and implications of this work include identification of the biologic mechanisms which mediate the relation between stress and preterm birth as well as potential development of a prognostic risk assessment for preterm delivery.
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1 |
2002 — 2006 |
Wadhwa, Pathik D |
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. |
Stress Biology, Race/Ethnicity &Infection in Pregnancy @ University of California Irvine
DESCRIPTION (provided by applicant): Bacterial vaginosis (BV), the most common reproductive tract infection in pregnancy, is associated with an increased risk for preterm birth. The determinants of susceptibility for developing BV and infection-related preterm birth are not well understood. Moreover, the causes of racial/ethnic differences in the prevalence and sequella of BV are largely unexplained. We propose a biobehavioral framework to study these issues, with the central hypothesis that prenatal stress, operationalized as a biological construct, heightens susceptibility for acquiring BV and potentiates its pathophysiological consequences. We focus on the maternal-placental-fetal endocrine and immune-inflammatory processes as the primary mechanisms of interest because both systems play a critical role in regulating susceptibility to infection, participate in the physiology and pathophysiology of term and preterm parturition, and are highly responsive to stress. We propose a longitudinal, cohort study of 900 African-American, Hispanic and nonHispanic White pregnant women to assess the prevalence of BV at two time points during early and mid gestation, quantify the endocrine and immune-inflammatory milieu at each of these times, measure behaviors known to be associated with the acquisition of BV, and follow subjects through delivery. BV status will be assessed by Gram stained vaginal smears. Endocrine stress parameters will be assessed by measures of cortisol, corticotropin-releasing hormone (CRH), and estriol (E3). Immune-inflammatory process will be quantified from responses of the cytokines interleukin (IL)-1, IL-6, TNFalpha, IL-10 and IL-12 to bacterial endotoxin (LPS) challenge using ex-vivo whole blood tissue culture system. Our specific aims are to examine: (1) the role of endocrine stress physiology in increasing susceptibility to developing bacterial vaginosis (BV) in pregnancy, and the role of immunosuppression as a mediator of this effect; (2) the role of endocrine stress physiology in increasing the susceptibility of BV+ women for spontaneous preterm birth, and the role of pro-inflammatory immune responses as a mediator of this effect; and (3) the extent to which stress-related endocrine and immune processes account for racial/ethnic disparities in prevalence of infection and infection-related preterm birth The scientific significance of this proposal pertains to elucidating biological mechanisms that determine susceptibility or vulnerability for developing reproductive tract infection in pregnancy and its adverse consequences (preterm birth), and clarifying the physiological basis for the observed effects of race/ethnicity on these outcomes. The practical significance of this proposal is the development and assessment of new ways (e.g., the ex-vivo immune challenge methodology) to identify women who are at heightened risk for infection and infection-related preterm birth, thereby improving obstetric risk assessment.
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1 |
2004 — 2006 |
Wadhwa, Pathik D |
M01Activity Code Description: An award made to an institution solely for the support of a General Clinical Research Center where scientists conduct studies on a wide range of human diseases using the full spectrum of the biomedical sciences. Costs underwritten by these grants include those for renovation, for operational expenses such as staff salaries, equipment, and supplies, and for hospitalization. A General Clinical Research Center is a discrete unit of research beds separated from the general care wards. |
Mothers and Babies Health and Well-Being Study @ University of California San Diego |
0.981 |
2004 — 2006 |
Wadhwa, Pathik D |
M01Activity Code Description: An award made to an institution solely for the support of a General Clinical Research Center where scientists conduct studies on a wide range of human diseases using the full spectrum of the biomedical sciences. Costs underwritten by these grants include those for renovation, for operational expenses such as staff salaries, equipment, and supplies, and for hospitalization. A General Clinical Research Center is a discrete unit of research beds separated from the general care wards. |
Uci Women's Biobehavioral Processes and Health Study @ University of California San Diego |
0.981 |
2005 — 2009 |
Wadhwa, Pathik D |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Overall - Gene-Environment Interactions in Human Parturition @ University of California-Irvine
DESCRIPTION (provided by applicant): This Program Project, entitled Gene-Environment Interactions in Human Parturition, proposes to evaluate the utility of information about DMA sequence variation and function in candidate susceptibility genes to understand and predict the risk of preterm birth and racial/ethnic disparities in its prevalence. Our goal is to develop a genotype/phenotype resource and analytical strategies to identify the genetic and environmental determinants of the length of human gestation/ tinning of onset of spontaneous parturition, and to model the gene, environment, and maternal-fetal interactions that may underlie the risk of preterm birth among three racial/ ethnic populations: African-Americans, Hispanics and nonHispanic Whites. The genetic architecture of parturition is defined as the number of loci, their genomic positions, the number of functional alleles per locus, and the patterns of dominance, epistasis, pleiotropy, and geneenvironment interactions that characterize the transition from genotype to phenotype. Because the genetic architecture of parturition may vary among populations as a function of the heterogeneity of the relative frequencies of genetic and environmental effects, population-specific models will be developed in our analysis. Our research program will consist of three separate but inter-linked projects that propose and empirically test hypotheses, and four cores that provide the requisite resources for each of the projects. Project 1 - Population Structure of Genetic Variation in Pregnancy (James Hixson, PI) - will determine the full extent and distribution of genetic variation in the 16 candidate genes of interest among and between the three target racial/ethnic populations. Project 2 - Genotype- Phenotype Relationships in Human Parturition (Charles F. Sing, PI)- will examine genotype-phenotype associations to determine which subset of fetal and maternal genetic variations, in combination with specific environmental factors, predict measures of intermediate physiology and clinical end points in each of the three target racial/ethnic populations. Project 3 - Functional Significance of Genetic Variation in Pregnancy (Pathik D. Wadhwa, PI) - will characterize the functional relationships between maternal and fetal genetic variation and the dynamics of parturitionand stress-related physiological processes in vivo. The four cores are A) Administrative Core (Pathik Wadhwa, Director), to serve as an administrative office for the central co-ordination of all project and core activities (will include an Executive Committee and Internal and External Advisory Boards);B) Clinical Core (Calvin J. Hobel, Director) to collect clinical measures on 1,200 maternal-infant dyads, including DNA samples and measures of intermediate physiology, clinical end points and environmental risk factors;C) Genotyping Core (James E. Hixson, Director) to extensively resequence the 16 candidate genes and genotype 1,200 maternal-fetal DNA samples and unlinked genomic control polymorphismic markers;and D) Database Management and Statistical Analysis Core (Charles F. Sing, Director) to maintain a central study database and execute statistical analyses for all projects.
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1 |
2008 — 2009 |
Wadhwa, Pathik D |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Admin Core @ University of California Irvine
African American; Afro American; Afroamerican; Birth; Black Populations; Black or African American; Collaborations; Comment; Comment (PT); Comment [Publication Type]; Commentary; Commentary (PT); Decision Making; Editorial Comment; Editorial Comment (PT); Ensure; Environment; Environmental Factor; Environmental Risk Factor; Genes; Genetic; Genotype; Gestation; Goals; Hispanic Populations; Hispanics; Hispanics or Latinos; Human; Human, General; Investigators; Latino Population; Length; Man (Taxonomy); Man, Modern; Modeling; NICHD; National Institute of Child Health and Human Development; Neuroendocrine; Neuroendocrine System; Neurosecretory Systems; Parturition; Pathway interactions; Physiologic; Physiological; Population; Pregnancy; Premature Birth; Preterm Birth; Process; Programs (PT); Programs [Publication Type]; Published Comment; Research; Research Personnel; Researchers; Risk; Score; Spanish Origin; Time; Universities; Viewpoint; Viewpoint (PT); black American; environment effect on gene; environmental risk; fetal; gene environment interaction; hispanic community; maternal stress; pathway; premature childbirth; premature delivery; preterm delivery; programs; racial and ethnic; racial/ethnic; stressed mothers
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1 |
2008 — 2009 |
Wadhwa, Pathik D |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Functional Significance of Genetic Variation in Pregnancy @ University of California Irvine
ACTH; ACTH (1-39); ACTH-Releasing Factor; Adrenocorticotropic Hormone; Adrenocorticotropin; Aeroseb-HC; African American; Afro American; Afroamerican; Area Under Curve; Articulation; Assay; Awareness; Awarenesses; Behavioral; Bioassay; Biochemical; Biologic Assays; Biological; Biological Assay; Birth; Black Populations; Black or African American; Blood; CRF-41; CRH; California; Candidate Disease Gene; Candidate Gene; Categories; Cetacort; Chemotherapy-Hormones/Steroids; Clinical; Clinical Data; Complex; Condition; Consent; Cort-Dome; Cortef; Cortenema; Corticoliberin; Corticotropin; Corticotropin (1-39); Corticotropin Releasing-Factor Receptors; Corticotropin-Releasing Factor; Corticotropin-Releasing Factor-41; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Corticotropin-Releasing Hormone-41; Cortisol; Cortispray; Cortril; Critical Paths; Critical Pathways; DNA; DNA Sequence; Data; Data Banks; Data Bases; Databank, Electronic; Databanks; Database, Electronic; Databases; Deoxyribonucleic Acid; Dermacort; Diagnosis, Ultrasound; Discipline of obstetrics; Dysfunction; ENV; Echography; Echotomography; Eldecort; Elements; Endocrine; Endocrine Gland Secretion; Endocrine Physiology; Environment; Epidemiologic Research; Epidemiologic Studies; Epidemiological Studies; Epidemiology Research; Ethnic Origin; Ethnic group; Ethnicity; Ethnicity aspects; Event; Exposure to; Feedback; Fetus; Follow-Up Studies; Followup Studies; Frequencies (time pattern); Frequency; Functional disorder; Funding; Gene Proteins; Gene variant; Genes; Genes, env; Genetic; Genetic Diversity; Genetic Predisposition; Genetic Predisposition to Disease; Genetic Susceptibility; Genetic Variation; Genotype; Gestation; Glucocorticoid Receptor; Goals; Gravid; Head and Neck, Saliva; Health; Hispanic Populations; Hispanics; Hispanics or Latinos; Hormone Receptor; Hormones; Human; Human, General; Hydrocortisone; Hydrocortone; Hytone; Immune; Individual; Individual Differences; Infant; Inflammatory; Inherited Predisposition; Inherited Susceptibility; Interview; Joints; Knowledge; Laboratories; Latino Population; Length; Man (Taxonomy); Man, Modern; Maternal and Child Health; Measures; Mediating; Medical Imaging, Ultrasound; Medical Records; Modeling; Neuroendocrine; Neuroendocrine System; Neurosecretory Systems; Nutracort; Obstetrics; Organism-Level Process; Organismal Process; Outcome; Participant; Parturition; Pathway interactions; Patient currently pregnant; Patient pregnant NOS; Patients; Pattern; Phenotype; Physiologic; Physiologic Processes; Physiological; Physiological Processes; Physiology; Physiopathology; Placental Hormones; Play; Population; Predisposition; Pregn-4-ene-3,20-dione, 11,17,21-trihydroxy-, (11beta)-; Pregnancy; Pregnancy Outcome; Pregnancy not delivered; Pregnancy, gravid; Pregnant Women; Premature Birth; Preterm Birth; Probability; Procedures; Process; Proctocort; Production; Programs (PT); Programs [Publication Type]; Protein Gene Products; Protocol; Protocols documentation; Psychology, Physiologic; Psychology, Physiological; Psychophysiological; Psychophysiology; Psychosocial Stress; Publishing; Questionnaires; Race; Racial Group; Receptor Protein; Receptors, CRF; Receptors, CRH; Receptors, Corticotropin-Releasing Hormone; Recovery; Recruitment Activity; Relative Risks; Reporting; Reproductive Tract Infections; Research; Reticuloendothelial System, Blood; Risk; Risk Factors; Risks, Relative; Role; SUBGP; Saliva; Sampling; Social Conditions; Societal Conditions; Spanish Origin; Stocks, Racial; Stress; Structure; Subgroup; Susceptibility; Syndrome; Therapeutic Hormone; Therapeutic Hydrocortisone; Time; Trier Social Stress Test; Ultrasonic Imaging; Ultrasonogram; Ultrasonography; Ultrasound Test; Ultrasound, Medical; United States; Universities; Variant; Variation; Variation (Genetics); Work; abstracting; allelic variant; analytical method; base; biological adaptation to stress; black American; clinical data repository; clinical data warehouse; combinatorial; corticotropin releasing hormone; data repository; diagnostic ultrasound; env Genes; environment effect on gene; fetal; fetal stress; gene environment interaction; genetic etiology; genetic mechanism of disease; genetic vulnerability; hispanic community; in vivo; pathophysiology; pathway; pregnant; premature childbirth; premature delivery; prenatal stress; preterm delivery; programs; prospective; psycho-physiological; racial and ethnic; racial/ethnic; racial/ethnic difference; reaction; crisis; receptor; recruit; relational database; response; social; social role; social stress; sonogram; sonography; sound measurement; stress response; stress; reaction; stressor; therapeutic target; ultrasound; ultrasound imaging; ultrasound scanning
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1 |
2008 — 2009 |
Wadhwa, Pathik D |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Population Structure of Genetic Variation in Pregnancy @ University of California Irvine
0-11 years old; ACTH-Releasing Factor; African American; Afro American; Afroamerican; Allele Frequency; Alleles; Allelomorphs; Biology; Birth; Black Populations; Black or African American; CRF-41; CRH; CRH gene; Candidate Disease Gene; Candidate Gene; Cell Line; Cell Lines, Strains; Cell hybridization; CellLine; Child; Child Youth; Children (0-21); Chromosomes; Clinical; Complex; Condition; Corticoliberin; Corticotropin-Releasing Factor; Corticotropin-Releasing Factor-41; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone-41; Cytokines and Inflammatory Response; DNA; DNA Resequencing; DNA Sequence; Data; Deoxyribonucleic Acid; Diploid; Diploidy; Embryonic Tissue, Placenta; Endocrine; Environmental Factor; Environmental Risk Factor; Error Sources; Ethnic group; Frequencies (time pattern); Frequency; Gene Frequency; Gene variant; Genes; Genetic; Genetic Diversity; Genetic Heterogeneity; Genetic Polymorphism; Genetic Structures; Genetic Variation; Genetic analyses; Genotype; Gestation; Goals; Haploid; Haploid Cells; Haploidy; Haplotypes; Health, Reproductive; Hispanic Populations; Hispanics; Hispanics or Latinos; Human, Child; Hybrid Cells; Individual; Inflammatory Response Pathway; Instrumentation, Other; Latino Population; Method LOINC Axis 6; Methodology; Mexican; Modeling; Molecular; Molecular Genetic; Molecular Genetics; Mothers; Neuroendocrine; Neuroendocrine System; Neurosecretory Systems; Non-Hispanic; Not Hispanic or Latino; Nucleotides; Outcome; Parturition; Pathway interactions; Pattern; Phase; Phenotype; Placenta; Placenta-Tissue, Cells; Placentoma, Normal; Placentome; Polymorphism (Genetics); Polymorphism, Genetic; Population; Pregnancy; Premature Birth; Preterm Birth; Prevalence; Relative; Relative (related person); Reproductive Health; Research; Research Resources; Resequencing; Resources; Sampling; Sampling Studies; Somatic Cell Hybrids; Sources, Error; Spanish Origin; Structure; Testing; United States; Variant; Variation; Variation (Genetics); abstracting; allelic frequency; allelic variant; association test; base; black American; children; corticotropin releasing hormone; cost; cultured cell line; environmental risk; fetal; genetic analysis; genetic association; genetic structure of population; genetic variant; hispanic community; hybrid cell; improved; innovate; innovation; innovative; instrumentation; pathway; polymorphism; population genetic structure; premature childbirth; premature delivery; preterm delivery; race differences; racial and ethnic; racial and ethnic disparities; racial difference; racial/ethnic; racial/ethnic difference; reproductive; youngster
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1 |
2010 — 2014 |
Wadhwa, Pathik D |
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. |
Ema Assessment of Biobehavioral Processes in Human Pregnancy @ University of California-Irvine
DESCRIPTION (provided by applicant): Adverse birth outcomes (reduced length of gestation/ impaired fetal growth) are recognized as the most significant problem in maternal-child health in the United States. A substantial body of empirical evidence in animals and humans suggests that high levels of maternal psychosocial stress in pregnancy constitute an independent risk factor for these adverse outcomes. However, the translation of this knowledge from the population to individual level for risk assessment and intervention is limited by the fact that the commonly-used self-report, retrospective recall measures of stress have low sensitivity and specificity in predicting adverse birth outcomes. Two major weaknesses of the stress and birth outcome literature relate to (a) limitations in the traditional approach to assess maternal psychosocial stress, and (b) the failure to assess and account for individual differences in biological stress responsivity. Recent advances in ecological momentary assessment (EMA) sampling methods now afford the opportunity of assessing the dynamic interplay of psychological, behavioral and biological processes in natural settings to address shortcomings and knowledge gaps in this literature. We propose to import and adapt these methods into the area of behavioral perinatology research. Our specific aims are: 1) To estimate the magnitude of the effect of maternal psychosocial stress on a) maternal-placental-fetal (MPF) hormonal parameters, and b) birth outcomes; 2) To estimate the magnitude of the effect of maternal biological stress reactivity on a) MPF hormonal parameters, and b) birth outcomes; and 3) To determine whether the magnitude of the effect of maternal stress is modulated by the stage in gestation of occurrence of stress. Complete prospective data will be collected in a sample of at least 120 pregnant women over three 4-day assessments in early, mid and late gestation. Electronic diaries (PDAs) will be used to collect 15 measures/day of subjects' psychological state and other contextual information. Continuous ambulatory measures of maternal heart rate, respiration and physical activity, as well as seven saliva samples over the course of each day, will be collected for indicators of autonomic and endocrine activity. At the end of each ambulatory session, a maternal blood sample will be collected for measures of MPF endocrine mediators (CRH, E3). These data will be merged in time-synchronized datasets; time-invariant and time-variant variables will be computed by methods including subject-specific auto-regression models, and multivariate and longitudinal regression analysis will be employed to test the specific aims and hypotheses using generalizing estimating equations (GEE) and multi-level mixed models with fixed and random effects (hierarchical linear models; HLM). The scientific significance of our proposal pertains to understanding psychobiological mechanisms that are likely determinants of individual vulnerability for stress-related adverse birth outcomes, whereas the public health significance of this research pertains to the development and assessment of new measures and methodologies that will increase the specificity and sensitivity of biopsychosocial risk assessment and provide an empirical basis for the development and evaluation of comprehensive intervention strategies to reduce the unacceptably high incidence of adverse birth outcomes. Findings from our study also will inform the proposed psychobiological stress assessment protocol of the National Children's Study (NCS).
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1 |
2013 — 2014 |
Entringer, Sonja Wadhwa, Pathik D |
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. |
Prenatal Stress Biology, Infant Body Composition and Obesity Risk @ University of California-Irvine
DESCRIPTION (provided by applicant): The goal of our study is to examine the influence of adverse intrauterine conditions, or prenatal stress, on newborn and infant body composition and obesity risk. Obesity is one of the most important health issues facing our nation. The underlying causes at the individual level, and the reasons for its rapid increase in the population are not well-understood. Evidence suggests that the origins of obesity and its sequelae can be traced back to the intra-uterine period of life, at which time exposure to suboptimal conditions during development may result in fetal programming of physiological systems that then confer increased risk for obesity in childhood and adult life. The overwhelming majority of human epidemiological studies of fetal programming of obesity have relied on measures of either size at birth (such as low birth weight or small-for-gestational age birth), or fetal and early postnatal growth velocity, as markers of adverse intrauterine exposures. We propose an innovative and novel application of the fetal programming paradigm by emphasizing the use of a set of stress-related intrauterine maternal-placental-fetal (MPF) biological processes as the principal markers of exposure to intrauterine insult because MPF biological stress parameters may act as sensors of the quality of the intrauterine environment as well as transducers of its effects on the developing fetus and subsequent childhood and adult obesity risk. The specific questions addressed in our study include the following: (1) Do MPF indices of prenatal stress exposure over human gestation predict newborn body composition and change in body composition from birth until 6 months age, after accounting for the effects of other established risk factors for obesity? (2) Are there sensitive periods during gestation when the developing fetus is particularly vulnerable to the effects of prenatal biological stress on body composition? (3) Are MPF biological stress measures of the intrauterine environment more specific and sensitive predictors of newborn and infant body composition than currently-used measures of birth outcomes or fetal and early postnatal growth? (4) What are the consequences of MPF endocrine/immune-related changes in body composition on metabolic function (insulin sensitivity)? (5) Are the effects of prenatal biological stress on body composition mediated through a change in energy balance homeostasis set points and energy flux over time? We propose to conduct a prospective, longitudinal, follow-up study in a population-based cohort of infants born to mothers who will participate in a NIH-funded study of biological and behavioral processes in pregnancy. We will have extensive characterization in this infant cohort over the course of their intrauterine life and birth with all the prenatal measures required to address the above questions, including serial measures of the maternal-placental- fetal endocrine and immune/inflammatory milieu, serial ultrasound-based measures of fetal biometry, clinical measures of obstetric complications, measures of maternal biophysical, sociodemographic, behavioral, psychosocial characteristics, and measures of the birth phenotype. From this cohort we will recruit a sample of 120-140 children at birth and follow them up until 6 months age. We propose two major study assessments at T1=0-2 weeks and T2=6 months age. At each assessment our primary study outcome, child body composition, will be quantified by dual energy x-ray absorptiometry (DXA); total energy expenditure (TEE) will be quantified using the doubly labeled water (DLW) method; and metabolic function (insulin sensitivity) will be quantified from measures of blood glucose and insulin. Infant nutrition and feeding practices will be assessed concurrently using multiple-pass 24h diet recalls. State-of-the-art statistical modeling techniques for parametric and non-parametric repeated measures, time- series data, including generalized additive models, polynomial distributed lag, classification and regression trees, and multivariate regression analysis will be used to address the study aims. The significance and impact of this study derives from the importance of achieving at a better understanding of the underlying causes for increased susceptibility for obesity, thereby informing the development of new markers for early identification of risk and targets for intervention.
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1 |
2013 — 2015 |
Buss, Claudia (co-PI) [⬀] Wadhwa, Pathik D |
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. |
Fetal Programming of the Newborn and Infant Human Brain @ University of California-Irvine
DESCRIPTION (provided by applicant): Alterations of normal brain structure and white matter integrity are known to underlie many neuropsychiatric, neurodevelopmental, and behavioral disorders. Although these brain disorders can produce alterations in brain morphology, the vulnerability hypothesis suggests it also is possible that the incidence of these disorders may, in part, be a consequence of pre-existing alterations in brain morphology. It is believed that the origins of many of these pre-existing alterations in brain morphology can be traced back to the fetal period of life, when the developing fetus responds to suboptimal conditions during critical periods of cellular proliferation, differentiation and maturation by producing structural and functional changes in cells, tissues and organ systems. The goal of this proposed research is to test specific hypotheses about the effects of in utero biological stress exposure on human brain morphology and white matter integrity at birth and over the first year of postnatal life. Our proposal emphasizes the use of maternal-placental-fetal (MPF) endocrine and inflammatory measures of stress over gestation as the principal marker of exposure to intrauterine insults. The specific aims addressed in our proposal relate to determining the impact of prenatal MPF endocrine (CRH, cortisol) and immune/inflammatory (IL-6, TNF-1) markers of intrauterine stress on brain morphology and white matter integrity at birth and over the first year of postnatal life, and to examine the interrelationships between intrauterine perturbations, brain volume and white matter integrity, and brain function. We propose to conduct a prospective, longitudinal, follow-up study in a population-based cohort of children born to mothers who will participate in an NIH-funded study of biological and behavioral processes in pregnancy. We will have extensive characterization in this child cohort over the course of their intrauterine life and birth with all the prenatal measures required to address the above questions, including serial measures of the maternal-placental- fetal endocrine and immune/inflammatory milieu, clinical measures of obstetric complications, laboratory results of clinical/diagnostic tests, measures of maternal sociodemographic, behavioral, and psychosocial characteristics, measures of the birth phenotype, and banked samples of maternal biologic tissue and extracted maternal and child DNA samples. We will recruit a sample of 120-140 children from this cohort at birth and follow them up until 12 months age. We propose two major study assessments at T1= 2-4 weeks and T2= 12 months age. Our primary study outcomes, brain morphology (size of the hippocampus, amygdala and prefrontal cortex) will be derived from serial MRI scans, and white matter integrity (fractional anisotropy along major white matter tracts: corpus callosum genu and splenium tracts and uncinate fasciculus) will be derived from serial DTI scans. For all predictor variables (CRH, cortisol, IL-6 and TNF-alpha), the area under the curve (AUC) will be estimated using General Additive Models (GAM) via cubic B-splines, which will be used as the predictors for measures of brain morphology and white matter integrity. In order to determine if there are particular time points during pregnancy that represent sensitive periods in predicting size of HC, AG and PFC, polynomial distributed lag models will be employed. Infants' mental and motor development will be assessed at concurrent time points (at T1 and T2) with the Bayley Scales of Infant Development. Mediation models will be applied to test whether alterations in the brain associated with MPF parameters account for the association between the same MPF parameters and BSID performance. By providing novel neuroimaging data in human newborns/young infants and linking these outcomes to well-characterized measures of the intrauterine and early postnatal environment, we suggest the study will set the stage for translational research with implications for early identification of risk/vulnerable populations, and will thereby inform the subsequent development of primary and secondary intervention strategies.
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1 |
2015 — 2019 |
Buss, Claudia (co-PI) [⬀] Fair, Damien A (co-PI) [⬀] Wadhwa, Pathik D |
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. |
Intergenerational Effects of Maternal Childhood Trauma On the Fetal Brain @ University of California-Irvine
DESCRIPTION (provided by applicant): Exposure to severe trauma in childhood such as physical or sexual abuse represents one of the most pervasive and pernicious stressors in society. Its sequelae, which may endure over the entire lifespan, include depression, PTSD, endocrine and immune function dysregulation, obesity, substance abuse, and also increased likelihood of subsequent exposure to trauma in adulthood. Moreover, emerging evidence suggests the long shadow cast by childhood trauma may not be restricted to only the lifespan of this vulnerable population of abused women, but also may be transmitted to another yet even more vulnerable population - their children - who then go on to exhibit an increased prevalence of neurodevelopmental and psychiatric disorders. Thus, a vicious cycle of perpetuation and possible amplification may become established. The prevailing view is that the intergenerational transmission from mother to child of the effects of maternal exposure to childhood trauma likely occurs after her child's birth via the effects of maternal dysfunctional states and behaviors (e.g. low maternal sensitivity, depression). We postulate that the process of intergenerational transmission may start earlier during the highly sensitive period of fetal development. In the current proposal we focus on the newborn child's brain stress circuit morphology and connectivity as the outcome of primary interest and on CT-related alterations in the maternal-placental-fetal (MPF) endocrine and immune stress biology as the proximate pathway of transmission. We propose to conduct a prospective, longitudinal study from early gestation till the neonatal period in a population-based cohort of approximately 200 mother-child dyads. We will collect serial measures of stress biology in early, mid and late pregnancy to characterize the endocrine (CRH, cortisol) and immune (CRP, IL-6) milieu at each trimester as well as their trajectories across gestation. We will acquire newborn brain scans to quantify the volumes of fronto-limbic regions (hippocampus, amygdala, prefrontal cortex) and their structural and functional connectivity as the primary outcomes of interest. Causal pathway models will be used to assess whether the effects of maternal CT exposure on her newborn's brain and mediated by MPF stress biology. Among CT+ women we will delineate the relative importance of psychiatric/psychological, behavioral and biophysical states and conditions in modulating the effects of CT exposure. This project addresses scientific and public health issues of critical importance. Our results will reveal new information about the health status of vulnerable populations and shed light on the mechanisms of intergenerational cycles of vulnerability. Our findings may suggest new avenues for early identification of at-risk individuals, as well as for th subsequent development and testing of prevention and intervention strategies to limit the intergenerational perpetuation of poor health and disadvantage. Study results will be disseminated through scientific publications and presentations at scientific conferences as well as at advanced training events for medical and social work personnel.
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1 |
2016 |
Entringer, Sonja Wadhwa, Pathik D |
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. |
Maternal Acculturation in Pregnancy and Infant Adiposity in Mexican Americans @ University of California-Irvine
PROJECT SUMMARY/ ABSTRACT This proposal addresses the compelling public health issue of the problem of childhood obesity in the Hispanic (Mexican-?American) population. In this context, one of the most striking epidemiological observations is that Hispanic immigrants in the U.S. exhibit a progressive and pronounced decline in health (obesity/ adiposity) over time and across generations that is evident even after accounting for socioeconomic status. The prevailing paradigm invokes the construct of acculturation (post-?migration acquisition of host culture and/or loss of heritage culture) and posits this health decline is a biological consequence of some of acculturation?s psychosocial and behavioral sequelae (increasing stress, declining social ties, adoption of unhealthy diet). However, research has overlooked one crucial point: a major feature of this phenomenon is its intergenerational component, and yet intergenerational transmission is unaddressed. Our proposal seeks to address this important limitation. We propose that the cause of the observed intergenerational escalation in obesity among Mexican-?Americans may, in part, originate during the intrauterine period of life. At this time, maternal acculturation-?related processes may impact fetal development to produce phenotypic alterations in the structure and function of cells, tissues and organ systems that increase susceptibility for obesity/adiposity (i.e., the concept of ?fetal/developmental programming of health and disease risk?). We propose to conduct a prospective, longitudinal study in a representative cohort of N=300 first-? and second-? generation Mexican-?American mothers and their offspring from early gestation through birth till 6-?month age. We will conceptualize, operationalize and analyze acculturation as a multi-?dimensional construct. We will quantify child adiposity (% fat mass) at birth and at 6-?mo age by dual-?energy X-?ray absorptiometry (DXA) whole-?body imaging. We will address the following specific aims: Aim 1: Test the hypothesis that maternal acculturation is prospectively associated with newborn and infant body composition (adiposity). Aim 2: Test the hypothesis that gestational endocrine (cortisol, CRH), immune (IL-?6, TNF-??, CRP), oxidative (5-?iPF2?-?VI), and metabolic (glucose, insulin) biology across pregnancy mediates the effect of maternal acculturation on newborn and infant body composition (adiposity). Aim 3: Identify and quantify the potentially modifiable maternal psychological, behavioral and biophysical characteristics that are associated with acculturation and may account for its impact on gestational biology and child body composition (adiposity). We have assembled an interdisciplinary team of established investigators with complementary expertise; performed a feasibility analysis documenting our ability to recruit and retain the proposed study population and implement all elements of the study protocol; and collected and present preliminary data in support of the key tenets of our proposal. Our study will generate new information about the health of Mexican Americans, shed more light on the causes and mechanisms of intergenerational cycles of vulnerability, and provide a basis for developing specific translational targets for future intervention studies.
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1 |
2016 — 2021 |
Buss, Claudia (co-PI) [⬀] Miller, Richard Kermit O'connor, Thomas G [⬀] Simhan, Hyagriv N Wadhwa, Pathik D |
UG3Activity Code Description: As part of a bi-phasic approach to funding exploratory and/or developmental research, the UG3 provides support for the first phase of the award. This activity code is used in lieu of the UH2 activity code when larger budgets and/or project periods are required to establish feasibility for the project. UH3Activity Code Description: The UH3 award is to provide a second phase for the support for innovative exploratory and development research activities initiated under the UH2 mechanism. Although only UH2 awardees are generally eligible to apply for UH3 support, specific program initiatives may establish eligibility criteria under which applications could be accepted from applicants demonstrating progress equivalent to that expected under UH2. |
Pre- and Postnatal Exposure Periods For Child Health: Common Risks and Shared Mechanisms @ University of Rochester
ABSTRACT There is rapidly growing evidence that the health and development of the child and adult can be traced to early environmental influences. However, the vast majority of the evidence is correlational: fundamental questions remain about which specific early exposures confer risk, when in development exposure may have significant and lasting influence, and the mechanisms of effects. This application to the Environmental Influences on Child Health Outcomes (ECHO) RFA (OD-16-004) synthesizes two recently initiated and highly compatible pediatric cohort studies in which environmental exposures are being tracked in 500 pregnant mothers from the 1st trimester; we are already collecting extensive prenatal biological samples and placental samples as well as detailed psychological, socio-demographic, and life history data. We especially target the prenatal period to examine if and how prenatal exposures may ?program? adaptive biological responses in the fetus and child, with carry-forward effects on brain and somatic health; furthermore, we focus particularly on inflammation as a mediator of environmental exposures because it is a compelling biological mechanism by which a wide range of exposures may shape child neurodevelopment and obesity. These data, which cover cellular mechanisms and social demography, will help translate how the range of environmental influences from pregnancy shape child health outcomes. The 500 children will be extensively studied at newborn, 6 months, 1 year, 2 years, 3 years, and 4 years of age using clinically derived and state-of-the-art behavioral, physical and biological assessments of neurodevelopment and obesity. In the UG3 phase we will harmonize protocol development across sites; complete collection of prenatal and a substantial majority of placental samples and perinatal outcomes across cohorts; commence collection of neonatal brain imaging and physical development outcomes. We will also develop models for the biological and social and demographic exposure data in preparation for analyses of child health outcomes in the UH3 phase. For the UH3 phase, we will characterize inflammation from multiple sources throughout pregnancy, in the placenta, and in early infant development to identify its psychosocial, developmental, and environmental exposure origins and sources. In addition, we will test alternative mechanisms by which prenatal exposures and indicators of inflammation predict perinatal outcomes, child obesity, and child neurodevelopment. We will also complete the complex task of biobanking extensive blood, urine, saliva and place samples on approximately 1,000 individuals and contributing the broader ECHO consortium research agenda. The proposed study will add significant new information to our understanding of which environmental influences may have causal influence on child health outcomes, and the timing and mechanisms of these effects. This information will provide a much-needed empirical foundation to know how and when in development to intervene to promote child health outcomes.
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0.958 |
2016 — 2020 |
Blackburn, Elizabeth H (co-PI) [⬀] Simhan, Hyagriv N Wadhwa, Pathik D |
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. |
Social Disadvantage and Fetal Programming of Newborn-Infant Telomere Biology @ Magee-Women's Res Inst and Foundation
? DESCRIPTION (provided by applicant): Population health disparities are evident from the earliest stages of the life, persist over the life span, and are perpetuated across generations. Their most salient determinant is exposure to social disadvantage. Research has elucidated how social disadvantage gets biologically embedded to impact disease risk over the life span, but little is known about how its effects are transmitted across generations. Our application addresses this important gap. We propose to investigate the process of intergenerational (mother-to-child) transmission of social disadvantage, with a focus on newborn and infant telomere biology as the primary outcome, the intrauterine period as the transmission time window, and maternal-placental-fetal (MPF) stress biology as the proximate transmission pathway. Telomere dynamics play a fundamental, causal role in the maintenance of genomic and cellular integrity, and telomere dysfunction represents perhaps the most salient antecedent cellular phenotype of disease risk for common, age-related disorders. Animal and human studies converge to support the critical importance of the initial (early life) setting of telomere length (TL) and telomerase activity (TA) for future health and disease risk, but little is currentl known about the determinants of this initial setting. Published and preliminary data by us and others provides biological plausibility for the novel concept that the initial setting of the telomre system is plastic and substantially influenced by developmental conditions. We hypothesize that, at the cellular level, the origins of health disparities may trace back, in part, to the effets of maternal social disadvantage on the on the initial setting of her child's telomere length and telomerase expression capacity, mediated by the programming actions of maternal-placental-fetal (MPF) endocrine, immune and oxidative stress biology. We propose to test this hypothesis in a prospective, longitudinal cohort study of N=1,000 child-mother dyads with serial measures across gestation and birth through the first year of life. Because race/ethnicity and socioeconomic status (SES) represent the principal proxy measures of social disadvantage, and because racial/ethnic differences in health are most pronounced between Non-Hispanic Blacks (hereinafter `Black') and Non-Hispanic Whites (hereinafter `White'), our proposed study population will include approximately equal numbers of Black and White mothers and their offspring. A unique strength of this population is the substantial variation in SES not only across but also within the two racial/ethnic groups, which will enable us to extricate their independent and combined (interaction) effects. We also will evaluate whether effects vary by the sex of the child. Specific Aims: A1: To test the hypothesis that maternal social disadvantage is prospectively associated with newborn and infant telomere biology. A2: To test the hypothesis that maternal-placental-fetal (MPF) stress biology mediates the effects of social disadvantage on newborn and infant telomere biology. A3: Identify and quantify the maternal psychological, behavioral and biophysical characteristics that are associated with social disadvantage and may account for its impact on newborn and infant telomere biology. The significance and impact of this study derives from the importance of better understanding the determinants and mechanisms underlying age-related disease risk in minority, disadvantaged populations (NIA Reversibility Initiative 2012) to inform translational research on early identification and intervention.
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0.903 |
2017 — 2020 |
Entringer, Sonja Wadhwa, Pathik D |
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. |
Maternal Acculturation in Pregcy and Infant Adiposity in Mexican Americans @ University of California-Irvine
PROJECT SUMMARY/ ABSTRACT This proposal addresses the compelling public health issue of the problem of childhood obesity in the Hispanic (Mexican-?American) population. In this context, one of the most striking epidemiological observations is that Hispanic immigrants in the U.S. exhibit a progressive and pronounced decline in health (obesity/ adiposity) over time and across generations that is evident even after accounting for socioeconomic status. The prevailing paradigm invokes the construct of acculturation (post-?migration acquisition of host culture and/or loss of heritage culture) and posits this health decline is a biological consequence of some of acculturation?s psychosocial and behavioral sequelae (increasing stress, declining social ties, adoption of unhealthy diet). However, research has overlooked one crucial point: a major feature of this phenomenon is its intergenerational component, and yet intergenerational transmission is unaddressed. Our proposal seeks to address this important limitation. We propose that the cause of the observed intergenerational escalation in obesity among Mexican-?Americans may, in part, originate during the intrauterine period of life. At this time, maternal acculturation-?related processes may impact fetal development to produce phenotypic alterations in the structure and function of cells, tissues and organ systems that increase susceptibility for obesity/adiposity (i.e., the concept of ?fetal/developmental programming of health and disease risk?). We propose to conduct a prospective, longitudinal study in a representative cohort of N=300 first-? and second-? generation Mexican-?American mothers and their offspring from early gestation through birth till 6-?month age. We will conceptualize, operationalize and analyze acculturation as a multi-?dimensional construct. We will quantify child adiposity (% fat mass) at birth and at 6-?mo age by dual-?energy X-?ray absorptiometry (DXA) whole-?body imaging. We will address the following specific aims: Aim 1: Test the hypothesis that maternal acculturation is prospectively associated with newborn and infant body composition (adiposity). Aim 2: Test the hypothesis that gestational endocrine (cortisol, CRH), immune (IL-?6, TNF-??, CRP), oxidative (5-?iPF2?-?VI), and metabolic (glucose, insulin) biology across pregnancy mediates the effect of maternal acculturation on newborn and infant body composition (adiposity). Aim 3: Identify and quantify the potentially modifiable maternal psychological, behavioral and biophysical characteristics that are associated with acculturation and may account for its impact on gestational biology and child body composition (adiposity). We have assembled an interdisciplinary team of established investigators with complementary expertise; performed a feasibility analysis documenting our ability to recruit and retain the proposed study population and implement all elements of the study protocol; and collected and present preliminary data in support of the key tenets of our proposal. Our study will generate new information about the health of Mexican Americans, shed more light on the causes and mechanisms of intergenerational cycles of vulnerability, and provide a basis for developing specific translational targets for future intervention studies.
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1 |
2019 — 2020 |
Thompson, Paul M (co-PI) [⬀] Thompson, Paul M (co-PI) [⬀] Wadhwa, Pathik D |
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.) |
Human Newborn Energy Homeostasis Brain Networks and Infant Adiposity @ University of California-Irvine
This revised application, submitted in response to NIH PA-18-741 ?Secondary Analyses in Obesity, Diabetes, and Digestive and Kidney Diseases,? relates to the public health problem of childhood obesity, with a specific focus on the characterization, determinants and role of energy balance homeostasis-related brain circuitry in the human newborn. The proposal describes a comprehensive plan designed to advance neonatal MRI analytical methods, developmental systems neuroscience, and fetal programming of health and disease risk. The critical importance of the hypothalamic-limbic-cortical brain circuitry that regulates energy homeostasis is well established, and MRI-based measures of energy homeostasis-related brain circuits have been associated with obesity outcomes. However, it is unclear whether the observed differences in these brain regions and circuitry in obese relative to normal-weight individuals are a cause, consequence, or both, of the obese state. Moreover, relatively little is known about the developmental ontogeny of these brain regions and circuitry, particularly during the fetal period, and their prospective role in shaping propensity for childhood obesity. This project addresses this fundamental knowledge gap. We will develop novel measures and conduct analyses using newborn brain imaging and other data elements from 4 inter-linked NIH-funded projects on prenatal stress and fetal programming of brain development and infant body composition (R01 HD-060628; R01 MH-091351; R01 HD-065825; UG3 OD-023349). The importance of selecting the newborn brain as the starting time point derives from the logic that brain circuitry at this time could not yet have been influenced by postnatal factors such as diet/feeding, thereby enabling the study to disentangle the temporality of effects. In a recent position paper on the pathogenesis of obesity, the U.S. Endocrine Society emphasized the need to conceptualize obesity as a disorder of the energy homeostasis system and elucidate its underlying mechanisms and developmental influences. Towards this objective, and using a population of ~100 mother-infant dyads followed from early gestation through birth till 5 yrs age, we will integrate research aims that leverage the resources of these projects to advance our understanding of the origins of childhood obesity. Aim 1. Develop measures of energy homeostasis brain circuitry using anatomical, diffusion and functional MRI. Because such measures have not yet been established in newborn homeostasis circuitry, this aim will fulfill an important need in terms of not only scientific knowledge but also technical capability. Aim 2. Address the physiological relevance and clinical significance of these novel MRI-based newborn brain measures by testing the hypothesis that measures of the human newborn?s energy homeostasis brain circuitry are prospectively associated with infant adiposity and subsequent childhood obesity risk. Aim 3. Identify the prenatal (gestational biology) determinants of variation in the measures of newborn brain energy homeostasis circuitry that are associated with infant adiposity. Significance. By identifying the role and determinants of energy homeostasis-related brain circuitry in the human newborn, these findings will ultimately provide the basis for the subsequent development of strategies aimed at the primary prevention of childhood obesity.
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