权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Project 3: Leukocyte-Mediated Regulation of Cardiorenal Syndrome

项目3：白细胞介导的心肾综合征调节

基本信息

批准号：
10612837
负责人：
Douglas Tilley
金额：
$ 43.59万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10612837
关键词：
Affect American Cardiac Cardiorenal syndrome Cells Cessation of life Characteristics Clinical Communication Detection Development Disease EFRAC Environment Fibroblasts Fibrosis Flow Cytometry G protein coupled receptor kinase G-Protein-Coupled Receptors Genetic Healthcare Heart Heart Injuries Heart failure Human Immunohistochemistry Infiltration Injury Intervention Kidney Laboratories Leucocytic infiltrate Leukocyte Trafficking Leukocytes Lymphocyte Macrophage Measurable Mediating Molecular Mus Myocardial dysfunction Myocardium Neurohormones Organ Pathway interactions Patients Phosphotransferases Physiological Play Population Prevalence Prevention Process Prognosis Receptor Signaling Regulation Reporting Resources Risk Factors Role Severity of illness Signal Transduction Structure Sympathetic Nervous System System Therapeutic Transcript Venous beta-2 Adrenergic Receptors beta-adrenergic receptor beta-arrestin clinically relevant cost cytokine fundamental research hemodynamics insight kidney cell kidney dysfunction kidney fibrosis leukocyte activation monocyte mortality neutrophil novel novel strategies peripheral blood pharmacologic prevent receptor receptor expression recruit repair strategy response single-cell RNA sequencing specific biomarkers transcriptome treatment strategy

项目摘要

Summary HF affects 6.5 million Americans, with almost 1 million new cases per year and costing over $30 billion in healthcare resources. Renal dysfunction (RD) is common in HF, with a reported prevalence over 50%, and is a major risk factor for death. Ultimately, cardiac dysfunction promotes renal fibrotic remodeling and progressive HF-induced RD, a pathophysiologic condition known as cardiorenal syndrome (CRS). Importantly, RD in HF is a potent marker of decreased survival, outperforming traditional metrics of HF disease severity like ejection fraction and functional class, however fundamental research into the mechanisms behind this process are limited. A number of factors preceding fibrosis contribute to the development of CRS, including changes in hemodynamics, neurohormones, cytokines and sympathetic nervous system (SNS) activation. Responsive to each of these changes are leukocytes, including neutrophils, monocytes, macrophages and lymphocytes, some of which have been implicated in CRS. However, few reports have investigated whether they play a reactionary or causative role in the development of CRS-induced renal dysfunction and remodeling in response to HF or how to mitigate their impact in this process. We hypothesize that leukocytes play a fundamental role in regulating CRS, and since RD remains a strong independent predictor for poor prognosis in HF patients, understanding the role of leukocytes and the molecular changes they undergo during CRS progression may offer new strategies by which to alleviate patient mortality. Therefore, we will determine the temporal- and subtype-specific leukocyte infiltration profiles in relation to changes in cardiac and renal structure and function during CRS progression, the impact of their deletion at specific timepoints, as well as perform a dynamic single cell transcriptome analysis of renal cells during CRS and transcriptome analyses of peripheral blood leukocytes from mice and humans with clinically-manifested CRS. In addition, our lab recently showed that modulation of leukocyte-specific β2-adrenergic receptor (β2AR) expression or signaling alters leukocyte targeting and responsiveness to injury in a GPCR kinase (GRK)/β-arrestin (βarr)-dependent manner. Thus, we will define the impact of leukocyte-specific β2AR-dependent signaling on CRS progression and determine how genetic deletion, pharmacologic inhibition or GRK/βarr-biased modulation of leukocyte β2AR signaling impacts CRS development and progression. Completion of this project will generate new molecular and physiologic insight toward the detection and treatment of HF-induced CRS via targeting of leukocyte-dependent processes and responsiveness.

总结