Multispecies Comparison of the Impact of Obesity on GVHD/GVT

肥胖对 GVHD/GVT 影响的多物种比较

基本信息

批准号：
9263536
负责人：
WILLIAM JOSEPH MURPHY
金额：
$ 63.07万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-12 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9263536
关键词：
Accounting Acute Graft Versus Host Disease Adult Adverse event Affect Allogenic Animal Model Anti-Inflammatory Agents Anti-inflammatory Applications Grants Autologous Body Composition Bone Marrow Transplantation Caloric Restriction Cancer Patient Cells Centers for Disease Control and Prevention (U.S.)Cessation of life Characteristics Chronic Clinic Clinical Clinical Trials Data Development Diet Disease Progression Ecology Equilibrium Functional disorder Graft-Versus-Tumor Induction Hematologic Neoplasms Hematopoietic Stem Cell Transplantation Human Immune Immune response Immune system Immunity Immunologics Immunotherapeutic agent Inbred Mouse Incidence Individual Indolent Infiltration Inflammation Inflammatory Inflammatory Response Intervention Intestines Investigation Light Link Mediating Mediator of activation protein Microbiology Modeling Molecular Target Morbidity - disease rate Mus Non obese Obese Mice Obesity Outcome Overweight Pathogenesis Pathologic Pathology Patient-Focused Outcomes Permeability Pharmacology Phenotype Play Population Preclinical Testing Process Production Publishing Radiation therapy Reaction Recovery Recruitment Activity Regimen Relapse Research Risk Role Symbiosis T cell response T-Lymphocyte Testing Therapeutic Therapeutic Intervention Thinness Toxic effect Transplantation Transplantation Conditioning aged base cancer type cell type cohort conditioning curative treatments cytokine experience germ free condition graft vs host disease high risk immunopathology immunoregulation inflammatory milieu macrophage microbial microbiome mortality nonhuman primate post-transplant disease pre-clinical prebiotics radiation response reconstitution response success targeted agent tumor tumor progression

项目摘要

We propose to build upon exciting preliminary data to modulate graft-versus-host disease (GVHD) and graft- versus-tumor (GVT) effects following allogeneic hematopoietic stem cell transplantation (HSCT) by understanding the role of obesity in the two processes. Currently, the vast majority of both HSCT and preclinical tumor studies involve the use of lean specific-pathogen-free (SPF) inbred mice. Obesity is a dynamic process that has been well defined to be immunomodulatory, and characteristically contains a “meta- inflammatory” environment, defined as a state of low-grade, chronic, self-sustaining inflammation. As cytokine storms from inflammatory cytokines play a critical component in GVHD pathophysiology, this grant application seeks to delineate the effects obesity as a pre-existing inflammatory condition on GVHD pathogenesis and GVT responses. Additionally recent investigation into the effects of obesity on commensal microbiome ecology and colonization of the gut have shed light onto the relationship between microbial diversity and immunopathology. Our application proposes the following three aims using a combination of mouse and non- human primate studies due to the unique ability to obtain obese non-human primates at UC Davis: 1) Evaluate the impact of obesity on the induction of inflammatory responses and pathology in response to conditioning regimens, and its effect on immune reconstitution post-autologous/syngeneic HSCT using mouse and non- human primate models, 2) to determine the impact of obesity on GVHD pathogenesis using murine and non- human primate models following allogeneic HSCT, and 3) to determine the effects of obesity on tumor progression and using the pharmacological and microbiological interventions affecting GVHD in the second aim, will determine effects on GVT.

我们建议以令人兴奋的初步数据为基础，以调节移植物抗宿主病（GVHD）和嫁接 - 同种异性造血干细胞移植（HSCT）的效果与肿瘤（GVT）效应了解肥胖在这两个过程中的作用。目前，HSCT和临床前肿瘤研究涉及使用瘦小特异性病原（SPF）近交小鼠的使用。肥胖是被很好地定义为免疫调节的动态过程，特征含有“ meta- 炎症环境，定义为低级，慢性，自我维持的注射状态。炎性细胞因子的暴风雨在GVHD病理生理学中起关键成分，该赠款应用旨在将肥胖症描述为对GVHD发病机理和 GVT响应。此外，最近对肥胖对共生微生物组生态学的影响的投资肠道的殖民化揭示了微生物多样性与免疫病理学。我们的应用建议使用小鼠和非 - 人类的灵长类动物研究由于独特的能力在加州大学戴维斯分校获得肥胖非人类灵长类动物的独特能力：1）评估肥胖对调节的炎症反应和病理诱导的影响方案及其对使用小鼠和非 - 人类灵长类动物模型，2）确定肥胖对使用鼠和非 - 同种异体HSCT之后的人类灵长类动物模型和3）确定肥胖对肿瘤的影响进展以及使用影响GVHD的药理学和微生物干预措施 AIM，将确定对GVT的影响。