PERIODONTAL DISEASE

牙周疾病

基本信息

批准号：
7622776
负责人：
LYNNAE Karen MILLAR Sauvage
金额：
$ 24.18万
依托单位：
UNIVERSITY OF HAWAII AT MANOA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2008-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7622776
关键词：
Acute Address Affect Age Alabama Alveolar Bone Loss Amniotic Fluid Anaerobic Bacteria Animal Model Antibiotics Antibodies Apoptosis Area Asians Bacterial Vaginosis Bacteriuria Bacteroides Biochemical Biological Assay Birth Birth Rate Blood Circulation Blood specimen Campylobacter Caring Case-Control Studies Cerebral Palsy Cervical Cervix Uteri Cessation of life Chromosome Pairing Chronic Chronic lung disease Clinical Cognitive Collaborations Communities Complete Hearing Loss Computer Retrieval of Information on Scientific Projects Database Condition Cross-Sectional Studies Cytomegalovirus DNA Probes Data Data Collection Databases Dental Hygiene Dental Schools Development Developmental Delay Disorders Diabetes Mellitus Dinoprostone Discipline of obstetrics Disease Distant Distress Elderly Encephalitis Endocrine Enrollment Environment Epidemiologic Studies Equilibrium Equipment Ethnic Origin Ethnic group Europe Evaluation Experimental Models Exposure to Fetal Growth Fetal Growth Retardation Fetal Lung Fetal Membranes Fetus Fever Fiber Funding Fusobacterium nucleatum Gardnerella vaginalis Gene Expression Genitourinary System Infection Genitourinary system Gestational Age Gingiva Gingivitis Goals Grant Growth Growth and Development function Hawaii Health Status Healthcare Heart Diseases Hemorrhage Hospitals Human Human Resources Immunoblotting Incidence Individual Infant Infection Infection of amniotic sac and membranes Infectious Agent Inflammation Inflammatory Inflammatory Response Institution Interferon Type II Intervention Trial Investigation Laboratories Lactobacillus Learning Learning Disabilities Length of Stay Link Literature Localized Low Birth Weight Infant Lung Measures Medicine Membrane Mentors Methods Mobiluncus Modeling Molecular Morbidity - disease rate Mothers NF-kappa B Necrosis Neonatal Neonatal Mortality Neurologic Neurons Newborn Infant North Carolina Numbers Observational Study Odds Ratio Oral Oral health Organ Organism Outcome Pacific Island Americans Pathogenesis Pathway interactions Patient currently pregnant Patients Perfusion Perinatal Perinatal Infection Periodontal Diseases Periodontal Infection Periodontitis Periventricular Leukomalacia Personal Satisfaction Phenotype Pilot Projects Placenta Play Pneumonia Population Porphyromonas gingivalis Postpartum Period Predisposition Pregnancy Pregnancy Outcome Pregnant Women Premature Birth Premature Labor Prematurity of fetus Prevalence Prevotella Prevotella intermedia Procedures Prospective Studies Protocols documentation Purpose Race Randomized Randomized Controlled Trials Range Rate Recording of previous events Reporting Reproductive Tract Infections Research Research Infrastructure Research Personnel Research Training Resources Respiratory distress Risk Risk Factors Rodent Model Role Rubella Rupture Sampling Secondary to Sepsis Syndrome Severities Shigella Infections Signs and Symptoms Smoking Smooth Muscle Source Specialist Stimulus Symptoms Synapses Systemic infection Techniques Technology Testing Thinking Time Tissues Training Transcriptional Activation Treponema denticola United States United States National Institutes of Health Universities Up-Regulation Uterus Vagina Week Whole Blood Woman Work Writing base body system career case control clinical Diagnosis concept cytokine design diabetic disability experience fetal follow-up gastrointestinal glycemic control in utero indexing innovation modifiable risk neonatal morbidity neonate non-diabetic oral infection oral plaque parity pathogen prenatal stress programs research study response skills stressor subcutaneous transmission process type I and type II diabetes white matter white matter damage

项目摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. INTRODUCTION This application is submitted in response to RFA NOT-RR-04-003. One of the purposes of this RFA is to increase research capacity by supporting junior investigators in career development in a focused area of research. For the last two years I have been working on a pilot study to investigate the role of periodontal disease in preterm birth among diabetic pregnant Asian and Pacific Islander women in conjunction with Dr. Steven Offenbacher, University of North Carolina. The present goal, with the experience gained from our prior pilot study, and with equipment, training, and data gained from this proposal, is to submit an R0-1 application in 2005. The aims for this two-year application are described below and the aims for the R0-1 are presented at the end of the proposal. A. SPECIFIC AIMS Pilot study specific aims (This will be a 2-year cross-sectional study) Objective 1: To determine the organisms associated with periodontal disease and gingival inflammation in pregnant diabetic and non-diabetic API women. Specific aim 1: The presence and level of key periodontal pathogens (P. gingivalis, T forsythenis, T. denticola, C. rectus, F. nucleatum, P. micros, P. intermedia, P. nigrescens, and possibly others) associated with periodontal disease and gingival inflammation in pregnant diabetic and non-diabetic API women will be ascertained from oral plaque samples. Hypothesis 1: Mothers with diabetes will have higher levels of P. gingivalis than non-diabetic women. Objective 2: Acute infections involving the genitourinary tract or distant organs have been implicated in preterm birth. This case-control study will determine the role of maternal infections in preterm birth in diabetic and non-diabetic API women. Specific aim 2: This small case control study will determine the presence and levels of vaginal and periodontal infections, as well as ascertaining perinatal cytomegalovirus transmission, among preterm birth and low birth weight deliveries in diabetic and non-diabetic API women. Hypothesis 2.1: The rate of preterm delivery and low birth weight will be higher in mothers with periodontal disease, as indexed by clinical signs and infectious burden, for both diabetic and non-diabetic women, regardless of whether there is a history of treated genitourinary tract infection, concomitant vaginal infections are present, or perinatal cytomegalovirus transmission has occurred. Hypothesis 2.2: The rate of preterm delivery and low birth weight will be higher in mothers with a history of genitourinary tract infection or vaginal infection at the time of delivery, as indexed by vaginal cultures, for both diabetic and non-diabetic women, regardless of oral health status or whether perinatal cytomegalovirus transmission has occurred. Hypothesis 2.3: The rate of preterm delivery and low birth weight will be highest in women with concomitant genitourinary infection and periodontal disease for both diabetic and non- diabetic women when these women are compared to all other groups. Objective 3: To determine if maternal acute or chronic infection results in neonatal mortality and morbidity. Specific aim 3: Infants delivered in the case control study described in Objective 2 will be examined at birth and throughout the newborns hospital stay to evaluate the role of maternal genitourinary tract infection, maternal periodontal disease, and perinatal cytomegalovirus transmission on the rate of neonatal death, chronic lung disease of prematurity or white matter damage. Hypothesis 3.1: Neonatal mortality and morbidity from the neonatal systemic inflammatory response syndrome, as indexed by neonatal death, chronic lung disease of prematurity or white matter damage, occurs secondary to one or more infections (maternal genitourinary tract infection, periodontal disease, and perinatal cytomegalovirus transmission) in API women. Objective 4: To provide research training, laboratory experience, and equipment necessary to conduct the proposed R01. Specific Aim 4.1: To train the study personnel including Dr. David Easa, Neonatologist, in standardized examination of the infants, and to establish appropriate enrollment procedures and data collection for the newborn exam and hospital course. Specific Aim 4.2: To train Dr. Lynnae Millar, PI and Maternal-Fetal Medicine Specialist, in microbiological assays (creation of DNA probes, DNA-DNA macroarray techniques, Checkerboard immunoblot antibody techniques, TLR-2, and NF-kappaB expression assays) needed to complete the R01 proposal, and to bring these assays to the University of Hawaii, thus building infrastructure at the University. Specific Aim 4.3: To purchase equipment necessary for biological assays and validate methods by comparing results with those at UNC to replicate the infrastructure technology capacity of UNC at the University of Hawaii. B. BACKGROUND AND SIGNIFICANCE Preterm delivery is a major healthcare problem affecting one in ten births and is the leading cause of neonatal death and long term disability. Diabetes among pregnant women is a well- established risk factor for preterm delivery. Ethnicity among Asian and Pacific Islander women in Hawaii clearly plays a role in both the rate of prematurity and the prevalence of diabetes. The association between Type 1 and Type 2 diabetes mellitus and periodontal disease is well documented.1,2 Most studies show a higher incidence and more severe forms of periodontal disease among diabetics than non-diabetics.3 Loss of alveolar bone and fiber attachment in diabetic patients with periodontal disease is greater than in non-diabetics.3 One study of 132 diabetic pregnant women demonstrated 96.2% of these patients had severe gingivitis or periodontitis. The intensity of the gingivitis increased as pregnancy progressed. Poor oral hygiene correlated with the progression of gingivitis during pregnancy.4 It is assumed that periodontal disease is more prevalent in Type 1 and Type 2 diabetic patients because they have a compromised ability to respond to infectious challenges. Alternatively, periodontal disease may exacerbate the diabetic condition, worsening glycemic control. The high rate of periodontal disease in pregnant diabetic women, a group with a high rate of adverse pregnancy outcome including preterm birth, makes this an optimal group to study in terms of periodontal infection, inflammation, and preterm birth. Infection, Inflammation and Preterm Birth The role of maternal periodontitis as a potential maternal-fetal stressor that has detrimental effects on the pregnancy outcome is a relatively new field of investigation. Early work with pregnant rodent models demonstrated that low-grade challenges with oral organisms during pregnancy resulted in impaired fetal growth. This was demonstrated using a chronic subcutaneous infection model with Porphyromonas gingivalis and also in a model of experimental periodontitis. In both models the infectious challenge was associated with an inflammatory challenge to the fetus, as measured by amniotic fluid PGE2 and TNF¿ and attendant growth restriction.5 Since there are no animal models of preterm birth, these data provided important proof-of-concept experiments that raised the possibility that distant, low grade oral infections might also trigger inflammation of the human maternal-fetal unit in a manner analogous to that seen with reproductive tract infections. The first reported human case-control study suggested that mothers with premature (37 weeks gestational age), low birth weight babies (under 2500g) had more severe periodontal disease than mothers with full term deliveries and that periodontitis appeared to confer considerable risk independent of other traditional obstetric risk factors.6 However, this investigation was a relatively small study of 124 cases and this case-control design did not permit the establishment of temporality of exposure (periodontal disease) as it relates to the outcome (preterm birth). Nonetheless, the potential magnitude of the effect of periodontal disease was surprisingly large (adjusted odds ratio 6.7, p=0.003) and provided impetus for further study prompting the conduct of prospective studies to appropriately measure attributable risk. A prospective study of about 1300 mothers conducted at the University of Alabama by Jeffcoat, Hauth and colleagues has confirmed that maternal periodontitis is an independent risk factor for preterm birth.7 These investigators reported that with increasing severity of periodontal disease as an exposure there is an increased risk for preterm birth with odds ratios in the range of 4-7 for severe periodontitis, adjusting for age, race, smoking and parity. Thus, maternal periodontitis as a potential risk factor for preterm birth appears to be gaining considerable supportive evidence, although additional case-control studies on low risk populations in Europe have not seen a relationship.8 Furthermore, two small independent studies have reported that providing periodontal treatments to pregnant women with periodontal disease may reduce the risk of preterm birth.9,10 In an observational study, Mitchell-Lewis suggested that mothers from a community-based group who received periodontal care from a dental school experienced a lower rate of prematurity than those not receiving care.9 An intervention trial by Lopez provides a more direct test of the association. 10 In this study, 390 mothers were randomly assigned to one of two groups - periodontal treatment prior to 22 weeks vs. delayed, postpartum treatment. The observed rate of preterm birth (37 weeks) was 10.2% in the untreated and 1.8% in the periodontal treatment group (p0.001). In total, these preliminary findings are encouraging and build a strong rationale for continuing the investigation examining the relationship between periodontal disease and abnormal pregnancy outcomes. Other localized or systemic infections have been implicated in preterm birth, and must be measured in any study examining the relationship between periodontal disease, inflammation, and prematurity. One of the more important acute exposures that has been implicated in preterm birth is an acute maternal genitourinary tract infection at some point during the pregnancy.11,12 Women with asymptomatic bacteriuria have twice the preterm births as non-colonized women. Bacterial vaginosis (BV) is a gram negative, predominantly anaerobic infection of the vagina, usually diagnosed from clinical signs and symptoms. It is associated with a decrease in the normal lactobacillus-dominated flora and an increase in anaerobes and facultative species including Gardnerella vaginalis, Mobiluncus curtsii, Prevotella bivia and Bacteroides ureolyticus. BV is a relatively common condition that occurs in about 10% of all pregnancies. It may ascend from the vagina to the cervix and even result in inflammation of the maternal-fetal membranes (chorioamnionitis). Extending beyond the membranes, the organisms may appear in the amniotic fluid compartment that is shared with the fetal lungs and/or may involve placental tissues and result in exposure to the fetal hematogenously. There is a clear epidemiological linkage between bacterial vaginosis and preterm birth, though randomized controlled trials looking at the effect of systemic antibiotics on the incidence of preterm birth have failed to show a positive effect.13 Acute infections involving distant organ systems, other than the genitourinary track, have been clearly shown to be capable of ultimately targeting the fetal-placental unit. The literature is replete with diverse examples of maternal primary distant infections that result in an abnormal pregnancy outcome, including rubella (endocrine), shigellosis (gastrointestinal), encephalitis (neurological) and pneumonia (pulmonary). 14 Most induce maternal cytokinemia and resultant fever that threatens the pregnancy and some of these infectious agents have been shown to target the placenta inducing local inflammation and necrosis. Some infectious agents that are abortofacient, such as Rubella and Campylobacter are capable of crossing the fetal placental barrier and result in direct exposure into the fetal circulation. Cytomegalovirus is such an agent, and is the most common vertically transmitted infection in the United States infecting .5 to 3% of all newborns.15 Most newborns born with the infection have no obvious signs or symptoms of the disease, though some develop signs and symptoms in later life. The most common manifestation of perinatal transmission in symptomatic newborns is partial or total deafness, though some infants are born with severe neurologic and developmental delays. Maternal systemic infections can elicit a local inflammatory response that results in inflammation of the maternal-fetal-placental unit including the uterus, the chorioamniotic membranes, the placenta, the amniotic fluid, the fetal lungs and the fetal circulation. These inflammatory stimuli induce hyperirritability of the smooth muscle of the uterus enhancing contractility, cervical thinning (effacement), cervical dilation and premature labor. Inflammation of the chorioamniotic membranes results in premature rupture. Infection and the resulting inflammatory response can also elicit damage to the placenta. Placental damage can cause areas of focal hemorrhage and necrosis and that results in poor fetal perfusion, fetal growth restriction and distress. Most of the obstetric predisposing conditions that result in preterm birth and growth restriction are thought to be orchestrated by a common biochemical effector pathway that has been initially described by Romero.16 An excellent review of these effector mechanism concepts with special application to periodontal disease was written by Curtis and colleagues.17 Infectious exposure to the mother during pregnancy is currently believed to be a significant factor that triggers in utero fetal stress that ultimately contributes to long-term growth and development problems that begin with the neonate and extend throughout the lifetime of the individual. The quality of the environment, as well as the duration of the gestation in utero has been suggested to be a critical determinant of long-term well being of the individual ranging from cognitive and learning skills to susceptibility of heart disease.18-21 Maternal infections during pregnancy and attendant inflammatory responses have been linked to specific neonatal problems including periventricular leukomalacia (PVL, white matter necrosis), respiratory distress (often leading to chronic lung disease of preterm birth) and cerebral palsy.18-21 Furthermore, increasing evidence suggest that the molecular and cellular inflammatory effector pathways that underlie the pathogenesis of preterm birth are also involved in growth restriction and developmental problems ranging from respiratory distress to cognitive and learning disabilities. For example, fetal neurological tissues are especially susceptible to damage via cytokines, such as interferon gamma, that induce apoptosis and impair synapse development of embryological neurons.22,23 Thus, the threat of maternal infectious exposures during pregnancy does not appear to be solely limited to effects on the duration of the pregnancy but also to neonatal growth and development. The goal of this pilot study is to determine which organisms are involved in periodontal disease in diabetic and non-diabetic API women. Additionally, data on the correlation between maternal genitourinary tract, maternal periodontal infection, and perinatal transmission of cytomegalovirus, with premature birth in diabetic and non-diabetic API, will be ascertained. Finally, the newborns will be examined after birth to obtain preliminary data on the effect of maternal infection on neonatal mortality and morbidity. In addition to obtaining pilot data for the subsequent R01 application, this proposal will allow us to standardize the neonatal examination, and establish a neonatal database and a neonatal follow up program. We will obtain equipment and training on methods for the microbiological assays that will be required for the R01, thus building infrastructure at the University of Hawaii. Summary of Rationale for Proposed Study Periodontal disease is likely to be a contributing factor towards the high rate of premature birth in diabetic women, and is a potentially modifiable risk factor contributing to the ethnic disparities in the rate of preterm delivery in this API population. However, to adequately assess the attributable risk of periodontal disease as an etiologic agent for preterm birth, other significant maternal genitourinary tract and perinatal infections need to be considered. We will be able to determine organisms involved in periodontal disease in diabetic and non- diabetic pregnant women from this study. Additionally, this cross-sectional study will enable us to obtain preliminary data on the role of infection and inflammation in diabetic patients delivering at term and preterm. This proposal will also allow us to establish a neonatal evaluation and follow up program, and to learn the technical assays and purchase equipment required to complete the planned R01 proposal. Innovation The collaboration and established mentoring occuring between UNC and UH has already been highly successful, as seen in the rapid progress in the pilot study to investigate the role of periodontal disease in preterm birth in diabetic pregnant Asian & Pacific Islander (API) women. The innovation is not in the methods that will be used in this project, but in the unique interdisciplinary consortium that has been established to address mechanisms underlying the disparity in preterm birth rates in API women. The use of diabetic pregnant patients to study infection, inflammation, and preterm birth is innovative and very relevant to our population as diabetes disproportionately affects Pacific Islanders. Pregnancy outcomes in diabetic Pacific Islanders are significantly worse than outcomes seen in diabetic women from other ethnic groups in Hawaii. UNC is currently pilot testing a protocol for establishing an inflammatory phenotype using a small whole blood sample. The method is suitable for large numbers of subjects seen in epidemiologic studies and will provide an ex-vivo snapshot of inflammatory responses characterizing innate and acquired (TH1 and TH2) responses using gene expression array methods. This technique will enable us to assess the up-regulation of inflammatory responses triggered by diabetes (via AGES/NF-KB) and shifts in TH1/TH2 balance which regulate pregnancy outcome. We expect to validate this method by the time the pilot study is completed.