Understanding longitudinal microbiome change in relation to immunologic outcomes in pediatric SCT recipients.

了解儿科 SCT 受者的纵向微生物组变化与免疫结果的关系。

• 批准号: 10350463
• 负责人: Caitlin Walfoort Elgarten
• 金额: $ 18.57万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10350463
• 关键词: Acute Graft Versus Host Disease; Address; Advisory Committees; Allogenic; Anti-Infective Agents; Antibiotics; Behavior; Bioinformatics; Biological Markers; Biology; Carbapenems; Cell physiology; Cells; Child; Childhood; Childhood Leukemia; Clinical; Clinical Research; Complex; Concentration measurement; Data; Development; Disease; Drug Kinetics; Drug Targeting; Engraftment; Ensure; Environment; Epidemiologist; Epidemiology; Event; Exposure to; Foundations; Future; Gastrointestinal tract structure; Goals; Healthcare; Hematological Disease; Hematopoietic System; Hemoglobinopathies; Human; Immune; Immune System Diseases; Immune system; Immunity; Immunologic Deficiency Syndromes; Immunologics; Individual; Infection; Intervention; Intervention Studies; Investigation; Kinetics; Knowledge; Lead; Leukocytes; Life; Link; Longitudinal Studies; Longitudinal cohort; Lymphopenia; Measurement; Measures; Mediating; Mentored Patient-Oriented Research Career Development Award; Mentorship; Metagenomics; Methods; Modeling; Nature; Neutropenia; Outcome; Pathogenesis; Patient-Focused Outcomes; Patients; Pediatric Hospitals; Pediatric Oncologist; Pediatric Oncology Group; Pediatric cohort; Pennsylvania; Peripheral; Pharmaceutical Preparations; Pharmacoepidemiology; Pharmacology; Philadelphia; Physicians; Physiological; Population; Prospective cohort; Quality of life; Recovery; Research; Research Personnel; Research Project Grants; Research Training; Residual state; Resources; Risk; Sampling; Savings; Scientist; Signal Transduction; Statistical Methods; Stem cell transplant; Supportive care; System; Systems Development; Therapeutic; Time; Training; Transplant Recipients; Transplantation and Immune System; Universities; Validation; Work; adverse outcome; base; behavioral study; bone marrow failure syndrome; career; clinically relevant; clinically significant; cohort; deep sequencing; experience; graft vs host disease; host microbiome; immune reconstitution; improved; infection risk; interpatient variability; kinetic model; leukemia; longitudinal analysis; microbiome; microbiome analysis; microbiome research; microbiome sequencing; microbiota; neutrophil; novel marker; patient oriented research; patient variability; pharmacodynamic model; prevent; rational design; response; skills; stem cells; success; therapy design

PROJECT SUMMARY/ABSTRACT This Mentored Patient-Oriented Research Career Development Award proposal will provide didactic and experiential training, expert mentorship, and an exceptional research environment to facilitate Dr. Caitlin Elgarten's development as an independent clinician scientist. Dr. Elgarten's long-term career goal is to develop strategies that use targeted measurement and manipulation of the microbiome to predict and prevent adverse outcomes of pediatric stem cell transplant (SCT). Although SCT offers a chance for cure for more than 1,500 children each year with life-threatening disorders of the hematologic and immune systems, the success of this treatment is limited by aberrant and/or delayed recovery of the new immune system leading to graft-versus-host disease (GVHD), serious infection and reduced survival. In this proposal, Dr. Elgarten will leverage data from three pediatric cohorts to characterize the disruption of the gastrointestinal tract microbiome that occurs during SCT. She will define the microbiome features that associate with acute GVHD and peripheral immune cell recovery, and identify the pharmacologic drivers of clinically relevant microbiome disruption. Through the adaptation of non-linear mixed effects models for repeated measures to model the multidimensional and highly dynamic nature of the microbiome, this study will deliver a greater understanding of the causal association of the microbiome and immune events after SCT. In doing so, this work will lay the foundation for identification of novel biomarkers and the rational design of interventions to improve SCT outcomes. Execution of these aims will also provide the candidate with essential experience in conducting observational microbiome research and with critical training in the advanced bioinformatics and statistical methods necessary to study the interaction of the microbiome, pharmacologic exposures and clinical factors that define risk for adverse outcomes after SCT. The candidate is a pediatric oncologist and SCT physician with formal training in pharmacoepidemiology and a background in clinical research focused on supportive care in SCT. She aspires to bring her perspective as a clinician and epidemiologist to the study of longitudinal microbiome change in this complex clinical scenario. Dr. Elgarten's goals for the K23 program are: 1) conduct a patient-oriented research project that will yield clinically meaningful results, 2) acquire bioinformatics skills for the analysis of microbiome sequencing data, and 3) develop a platform for analysis of longitudinal microbiome data in SCT based on non-linear mixed effects models for repeated measures. She has assembled a strong mentorship and advisory team, led by Dr. Brian Fisher, and inclusive of national experts in microbiome-host biology, deep sequencing methods and bioinformatics, quantitative model-based methods, and translational epidemiology. This guidance, combined with the extensive resources available at the Children's Hospital of Philadelphia and the University of Pennsylvania, will ensure the accomplishment of the proposed research and training goals and Dr. Elgarten's successful transition to independent investigator.

项目总结/文摘