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

Molecular mechanisms regulating peripheral arterial disease pathobiology in chronic kidney disease

调节慢性肾病外周动脉疾病病理学的分子机制

基本信息

批准号：
10306326
负责人：
Terence E Ryan
金额：
$ 58.45万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10306326
关键词：
Activities of Daily Living Affect Amputation Aryl Hydrocarbon Receptor Atherosclerosis Biological Biology Blood Blood Vessels Blood capillaries Cardiovascular system Cell Respiration Cessation of life Chronic Chronic Kidney Failure Clinical Cytochrome P450 Data Dependovirus Development Diabetes Mellitus Disease Disease Outcome Electron Transport Endothelial Cells Endothelium Enrollment Enzymes Etiology Evolution Exposure to Foundations Future Gangrene Genetic Growth Health Hindlimb Human Impairment In Situ In Vitro Indican Ingestion Injury Ischemia Isolated limb perfusion Knock-out Knockout Mice Knowledge Kynurenic Acid Kynurenine Laboratories Lead Life Ligands Limb structure Link Lower Extremity Mediating Metabolism Mitochondria Modernization Molecular Molecular Genetics Mus Muscle Muscle Cells Muscle function Myopathy Natural regeneration Organ Outcome Oxidative Phosphorylation Pain Pathology Pathway interactions Patient-Focused Outcomes Patients Peripheral arterial disease Pharmacology Phenotype Pre-Clinical Model Production Reactive Oxygen Species Receptor Activation Receptor Signaling Recovery Renal function Respiratory physiology Rest Risk Risk Factors Role Signal Pathway Skeletal muscle injury Smoking System Testing Tissues Toxic effect Waste Products angiogenesis base claudication comorbidity density disorder control effective therapy experience experimental study hemodynamics human data improved indoleacetic acid insight knock-down limb amputation mitochondrial dysfunction molecular modeling mortality risk muscle necrosis muscle strength new therapeutic target novel novel therapeutic intervention patient population primary outcome receptor binding skeletal small hairpin RNA solute success symptomatology therapeutic development translational study wasting

项目摘要

PROJECT SUMMARY/ABSTRACT Peripheral artery disease (PAD) is caused by atherosclerosis in the lower extremities which leads to a spectrum of life-altering symptomatology, including claudication, ischemic rest pain, and gangrene requiring limb amputation. Complicating the etiology of PAD, patients typically present with comorbid conditions or risk factors that accelerate disease evolution and substantially worsen pathology contributing to increased mortality risk. Among these, chronic kidney disease (CKD) accelerates the development of atherosclerosis, decreases functional capacity, and increases risk of amputation or death, however the underlying biologic mechanism(s) are poorly understood and vastly understudied compared with other comorbidities (i.e. smoking and diabetes). We have uncovered a novel molecular pathway that may link CKD and PAD pathobiology. We find that many uremic metabolites, which accumulate in CKD, cause chronic activation of the aryl hydrocarbon receptor (AHR) which leads to disruption of the mitochondrial electron transport system that exacerbates ischemic muscle injury and impairs angiogenesis. Preliminary experiments demonstrate that genetic knockdown of the AHR is protective against uremic toxicity, whereas expression of a constitutively active AHR causes mitochondrial dysfunction. Thus, we propose to test the novel hypothesis that the chronic activation of the AHR pathway results in ischemic muscle injury and impaired angiogenesis, thereby linking CKD and PAD pathobiology. This hypothesis will be tested using muscle- and vascular-specific inducible knockout of the AHR as well as adeno- associated virus-mediated expression of the a constitutively active AHR in pre-clinical models of CKD/PAD. Finally, our recent human data indicate elevated AHR signaling in PAD patients with CKD. We propose to extend these findings to establish a clinical link between muscle health/function, mitochondrial energetics, and AHR signaling in human PAD patients. Success in these studies will provide mechanistic insight into the impact of CKD on PAD pathobiology, and would provide a novel target for therapeutic development aimed to treat a patient population that currently has few available options.

项目总结/文摘