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Modeling affinity maturation at molecular resolution

在分子分辨率下模拟亲和力成熟

基本信息

批准号：
9249907
负责人：
GARNETT H KELSOE
金额：
$ 157.27万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-15 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9249907
关键词：
Affinity Alleles Amino Acid Sequence Amino Acids Antibodies Antibody Affinity Antibody Avidity Antigens Apoptosis Apoptotic Area B-Lymphocytes Binding Cell Culture System Cells Characteristics Chromosomes Communities Complex Computer Simulation Computer software Computing Methodologies DNA Sequence Data Data Analyses Development Disabled Persons Education and Outreach Engineering Ensure Generation of Antibody Diversity Genes Genetic Transcription Genotype Goals HIV-1 Hemagglutinin Human Immunization Immunoglobulin Genes Immunoglobulin Somatic Hypermutation Immunoglobulin Variable Region Immunoglobulins Immunology Individual Influenza Kinetics Laboratories Light Maps Mature B-Lymphocyte Measurement Measures Mechanics Memory Methods Modeling Molecular Mus Mutate Mutation Outcome Population Population Genetics Postdoctoral Fellow Process Property Reaction Research Research Project Grants Resolution Resources Running Schools Source Statistical Data Interpretation Statistical Models Structure Structure of germinal center of lymph node System Training Transgenes Uncertainty Vaccination Vaccines Validation Work anthrax protective factor antigen antibody binding biophysical model design experience experimental study graduate student human subject influenza virus vaccine influenzavirus insight mathematical model model development novel novel strategies outcome prediction overexpression pathogen pathogen exposure programs public health relevance response seasonal influenza simulation success symposium vaccine development vaccine trial vaccinology

项目摘要

DESCRIPTION (provided by applicant): Eliciting effective affinity maturation is an essential component of efficacious humoral vaccines. Recent findings in vaccine development for influenza and HIV-1 suggest that success in these key areas will depend on the ability to influence affinity maturation to an extent not yet possible. Continuing advances in experimental methods for elucidating cellular interactions in the germinal center reaction now make it possible to understand and model selection in affinity maturation. The specific aims are organized around the major goal of developing and using a mathematical model through cycles of experimentation, development, prediction and validation. For all research aims, the antibodies and antibody clones used will be selected from among those isolated and characterized in human and murine vaccine studies. The model developed will include an accurate model of somatic hypermutation sequence- specific mutation rate. This model will be made possible through the use of mice engineered to express the same rearranged Ig gene in productive and non-productive, but mutating, forms. The model will contain statistically accurate models of the correspondence between amino acid mutations and changes in affinity due to these mutations. These models will be realized through the use of a novel high-throughput B-cell culture system that allows the isolation of light- chain/heavy-chain pairs from individual B cells as well as measurement of the avidity of the antibody encoded by these genes. Furthermore, we will obtain the structures and detailed kinetic binding parameters for selected clonally related antibodies. The Ig variable-region genes to be used in these studies will be selected from genes isolated in a study of affinity maturation in the human response to seasonal influenza vaccine and in murine studies of influenza virus hemagglutinin or Bacillus anthracis protective antigen immunization. The models and methods obtained in these studies will then be used to study 1) the extent to which important features of affinity maturation are conserved in repeated experiments using controlled mouse studies as well as repeated vaccinations in human subjects; and 2) the effects on affinity maturation of modulating the effective selection intensity in mice engineered to overexpress an anti-apoptotic gene. We will provide cross-disciplinary training in our own laboratories and through summer schools and symposia. All models and software will be shared with the scientific community.