Functions of Lactoferrin Polymorphisms in an Oral Infection

乳铁蛋白多态性在口腔感染中的功能

基本信息

批准号：
7893469
负责人：
Kabilan Velliyagounder
金额：
$ 19.5万
依托单位：
UNIV OF MED/DENT OF NJ-NJ DENTAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7893469
关键词：
Adolescent Affect African American Alanine Alveolar Bone Loss Anti-Bacterial Agents Anti-Inflammatory Agents Anti-inflammatory Binding Biochemical Bone Resorption Characteristics Codon Nucleotides Crossbreeding Data Development Diagnostic Disease Epithelial Cells Exhibits Figs - dietary Genes Genetic Polymorphism Human In Vitro Incidence Individual Infection Inflammation Mediators Inflammatory Response Interferons Interleukins Jordan Knock-out Knockout Mice Lactoferrin Lead Leukocytes Lysine Mediator of activation protein Messenger RNA Minority Molecular Mus Oral Pathogenesis Patients Periodontal Diseases Periodontitis Play Positioning Attribute Predisposition Prevention approach Production Proteins Recombinants Research Role Saliva Salivary Glands Single Nucleotide Polymorphism Streptococcus mitis Streptococcus mutans Testing Therapeutic Threonine Tissues Tooth Loss Toxic Shock Syndrome Transgenic Mice Tumor Necrosis Factor-alpha Tumor Necrosis Factors Variant Wild Type Mouse Work alveolar bone arginyllysine bactericide base beta-Defensins caucasian American compare effectiveness cytokine expression vector in vivo killings migration mouse model novel novel strategies null mutation oral infection parotid secretory protein premature promoter prophylactic public health relevance

项目摘要

DESCRIPTION (provided by applicant): Aggregatibacter actinomycetemcomitans (Aa) has been implicated as the causative agent of localized aggressive periodontitis (LAP), a severe form of periodontal disease that can lead to premature tooth loss in adolescents. This rapid form of periodontal disease affects more than 70,000 adolescents annually in the US alone. African-Americans have a 15-fold greater incidence of the disease than Caucasian-Americans making LAP a disproportionate burden on minorities and the poor. We recently have identified two new polymorphisms of the lactoferrin (Lf) gene that are involved in LAP. One polymorphic alteration occurs at the codon 11 (alanine/threonine) and the other is localized in the LPS binding region at codon 29 (arginine/lysine). Preliminary data suggests that genetic polymorphisms of Lf may play a significant role in determining an individual's susceptibility to the LAP. The research outlined in this revised proposal will test this hypothesis using a mouse model and focusing on the functional characterization of genetic polymorphisms of Lf. The specific aims of the research are to 1) Generate bigenic Lf-variants/Lf-knockout mice; 2) Determine the anti-bacterial and anti-inflammatory activities against Aa colonization and infection in bigenic Lf-variants/Lf-/- and Lf-/- mice. The results of the proposed research will contribute to our understanding of the functional role of Lf polymorphisms in LAP and provide new approaches to prevention of this disease based on functional differences in single nucleotide polymorphisms (SNPs) in the Lf gene. PUBLIC HEALTH RELEVANCE: Aggregatibacter actinomycetemcomitans (Aa) has been implicated as the causative agent of localized Aggressive Periodontitis (LAP), a severe form of periodontal disease that can lead to premature tooth loss in adolescents. This rapid form of periodontal disease affects more than 70,000 adolescents in the US annually. African-Americans have a 15-fold greater incidence of disease than Caucasian Americans making LAP a disproportionate burden on minorities and the poor. Recently, we have identified two novel forms of genetic polymorphism of human lactoferrin. The alteration occurs at the codon 11 (Alanine (A)/Threonine (T) and other polymorphic alteration is localized in the LPS binding region of the Lf gene at the codon 29 (Argenine (R)/Lysine (K). Our preliminary results show that the A at position 11 and K at position 29 were predominantly found in LAP patients as opposed to T and R variants, respectively. The present proposal will test our hypothesis by focusing on the functional characterization of genetic polymorphism of Lf using a mouse model.

描述（由申请人提供）：聚集的放线菌Cetemcitans（AA）被认为是局部侵袭性牙周炎（LAP）的病因，这是一种严重的牙周疾病形式，可能导致青少年的过早牙齿脱落。这种快速形式的牙周疾病仅在美国就会影响70,000多名青少年。非裔美国人的疾病发病率比白人裔美国人高出15倍，这使膝盖对少数群体和穷人负担不成比例。我们最近确定了乳铁蛋白（LF）基因的两个新的多态性，它们涉及膝盖。一种多态性改变发生在密码子11（丙氨酸/苏氨酸），另一个多态性改变位于密码子29（精氨酸/赖氨酸）的LPS结合区域中。初步数据表明，LF的遗传多态性可能在确定个体对膝盖的敏感性方面起重要作用。该修订的提案中概述的研究将使用小鼠模型检验该假设，并着重于LF遗传多态性的功能表征。该研究的具体目的是1）产生bigenic lf-variants/lf-knockout小鼠； 2）确定临后LF-Varianiants/lf - / - 和LF - / - 小鼠的抗细菌和抗炎活性。拟议研究的结果将有助于我们理解LF多态性在膝盖中的功能作用，并基于LF基因中单核苷酸多态性（SNP）的功能差异，为预防该疾病提供了新的方法。公共卫生相关性：聚集的放线菌菌（AA）被认为是局部攻击性牙周炎（LAP）的病因，这是一种严重的牙周疾病形式，可导致青少年过早牙齿脱落。这种快速形式的牙周疾病每年在美国影响70,000多名青少年。非裔美国人的疾病发病率比白种人的疾病发病率高15倍，使膝盖对少数民族和穷人负担不成比例。最近，我们确定了人类乳铁蛋白的两种新型的遗传多态性形式。改变发生在密码子11（丙氨酸（a）/苏氨酸（T）和其他多态性变化位于LP基因29处的LF基因的LPS结合区域中（Argenine（r）/赖氨酸（k）。我们的初步结果表明，在位置29的位置29位于位置29的患者中，在LAP中占据了lap的变化。将通过小鼠模型专注于LF遗传多态性的功能表征来检验我们的假设。