Immune Dysregulation in Uremia

尿毒症的免疫失调

基本信息

批准号：
8383201
负责人：
NEAL B BLATT
金额：
$ 15.34万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-15 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8383201
关键词：
Activities of Daily Living Adult Advanced Development Affect Alveolar Macrophages Animal Model Anti-Inflammatory Agents Anti-inflammatory Apoptosis Aspergillus fumigatus Atherosclerosis Basic Science Biological Models Bone Marrow CD4 Positive T Lymphocytes Cardiovascular Diseases Cause of Death Cell surface Cells Child Chronic Chronic Kidney Failure Cytokine Gene DNA DNA Methylation Development Dialysis procedure End stage renal failure Epigenetic Process Etiology Future Gene Expression Genetic Heterogeneity Goals Health Helper-Inducer T-Lymphocyte Histone H3 Human ITGAM gene Immune Immune response Immune system Immunocompromised Host Immunosuppression Infection Inflammation Inflammatory Inflammatory Response Pathway Interferon Type II Interleukin-10 Interleukin-12 Interleukin-13 Interleukin-17 Interleukin-2 Interleukin-4 Interleukin-5 Kidney Failure Knowledge Lead Leukocytes Ligands Lung Lymphoid Methods Methylation Modality Modification Monitor Mus Natural Immunity Nephrectomy Nuclear Organ Patients Peritoneal Macrophages Public Health Receptor Activation Regulation Renal function Secondary to T cell response T-Lymphocyte TNF gene Testing Tissues Toll-Like Receptor 2 Toll-like receptors Toxin Translating Uremia adaptive immunity cardiovascular infection cell type cohort cytokine design fungus immune function improved in vivo insight macrophage mannose receptor mortality mouse model novel therapeutics pathogen prevent promoter research study response tissue culture translational study wasting

项目摘要

DESCRIPTION (provided by applicant): Chronic kidney failure, also known as end-stage renal disease (ESRD), results in the build-up of waste toxins that affect organs and tissues throughout the body, and causes significant mortality. The most common cause of death in chronic kidney failure is cardiovascular disease that results from chronic inflammation. Infections are the second most common cause of death in patients with ESRD, suggesting that ESRD results in alterations to the immune system. Previous attempts to understand these changes in immune function have focused on the characterization of circulating immune cells from relatively small numbers of patients with ESRD. As such, these studies are limited by multiple different causes for the kidney failure, and it is often not possible to distinguish the effect of kidney failure frm the effects of the dialysis used to replace kidney function. In order to gain a better understanding of the primary effect of kidney failure on immune function it may be valuable to use an experimentally reproducible model system. For this proposal, the well-established and reproducible mouse model of ESRD represented by 5/6 nephrectomy (SNx) will be used. In this proposal's first specific aim, macrophages, a key cell in the innate immune system, will be isolated from SNx and control mice. These macrophages will be examined in tissue culture to understand how chronic kidney failure primes the innate immune system to generate excess pro-inflammation. In the second specific aim, T- lymphocytes, the cell type responsible for directing immune responses, will be isolated from SNx and control mice, and examined in tissue culture to understand how chronic kidney failure alters adaptive immune responses. In the third specific aim, the immune systems of SNx and control mice will be challenged in vivo with the fungus Aspergillus fumigatus, which will serve as a model organism to probe pro-inflammatory immune responses that depend upon the coordinated activity of both innate and adaptive immunity. In all three aims, experiments will be conducted to isolate nuclear DNA from immune system cells to determine if the difference in their responses will be reflected in acquired modifications to their DNA (i.e. epigenetic alterations). The information gained from these studies is a first step in order to better understand how chronic kidney failure alters immune function, and how these alterations contribute to the high mortality in ESRD. Ultimately, it is hoped that these studies will lead to the development of new methods to reset immune responses in ESRD, and help to prevent both cardiovascular disease and lethal infections. PUBLIC HEALTH RELEVANCE: Cardiovascular disease and infections are the two leading causes of death in patients with chronic kidney failure, which affects at least 500,000 children and adults in the US. This proposal aims to improve the public health by using an animal model to gain insight into how chronic kidney failure alters the immune system in order to cause so much mortality. The ultimate goal of these basic science studies is to translate the findings to the bedside for new methods to prevent and treat lethal infections and reverse the chronic inflammation that causes cardiovascular disease.

描述（由申请人提供）：慢性肾衰竭，也称为终末期肾病（ESRD），会导致废物毒素积聚，影响全身器官和组织，并导致严重死亡。慢性肾衰竭最常见的死亡原因是慢性炎症引起的心血管疾病。感染是 ESRD 患者第二常见的死亡原因，这表明 ESRD 会导致免疫系统的改变。之前了解这些免疫功能变化的尝试主要集中在相对少数 ESRD 患者的循环免疫细胞的特征上。因此，这些研究受到肾衰竭的多种不同原因的限制，并且通常无法区分肾衰竭的影响与用于替代肾功能的透析的影响。为了更好地了解肾衰竭对免疫功能的主要影响，使用实验上可重复的模型系统可能很有价值。对于该提案，将使用以 5/6 肾切除术 (SNx) 为代表的成熟且可重复的 ESRD 小鼠模型。在该提案的第一个具体目标中，巨噬细胞（先天免疫系统中的关键细胞）将从 SNx 和对照小鼠中分离出来。这些巨噬细胞将在组织培养中进行检查，以了解慢性肾衰竭如何激发先天免疫系统产生过度的促炎症。在第二个具体目标中，将从 SNx 和对照小鼠中分离出 T 淋巴细胞（负责指导免疫反应的细胞类型），并在组织培养中进行检查，以了解慢性肾衰竭如何改变适应性免疫反应。在第三个具体目标中，SNx 和对照小鼠的免疫系统将在体内受到烟曲霉的挑战，该真菌将作为模型生物体来探测促炎性免疫反应，而促炎性免疫反应取决于先天性和适应性的协调活动。免疫。在这三个目标中，将进行实验从免疫系统细胞中分离出核 DNA，以确定它们反应的差异是否会反映在其 DNA 的后天修饰（即表观遗传改变）中。从这些研究中获得的信息是更好地了解慢性肾衰竭如何改变免疫功能以及这些改变如何导致 ESRD 的高死亡率的第一步。最终，希望这些研究能够开发出新方法来重置 ESRD 中的免疫反应，并有助于预防心血管疾病和致命感染。公共卫生相关性：心血管疾病和感染是慢性肾衰竭患者死亡的两大主要原因，慢性肾衰竭影响着美国至少 500,000 名儿童和成人。该提案旨在通过使用动物模型来深入了解慢性肾衰竭如何改变免疫系统从而导致如此高的死亡率，从而改善公众健康。这些基础科学研究的最终目标是将研究结果转化为临床应用，以找到预防和治疗致命感染以及逆转导致心血管疾病的慢性炎症的新方法。