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Role of JNK and BNP in Septic Hypotension

JNK 和 BNP 在脓毒性低血压中的作用

基本信息

批准号：
10265517
负责人：
Konstantinos Drosatos
金额：
$ 36.58万
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：
2020-09-20 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10265517
关键词：
Acute Address Adenoviruses Antibiotics Biochemical Biological Markers Blood Pressure Blood Volume Brain natriuretic peptide Cardiac Cardiac Output Cardiomyopathies Cessation of life Clinical Clinical Data Clinical Research Data Disease Disease Marker Disease Progression EFRAC Fiber Functional disorder Future Genes Genetic Goals Heart Heart failure Hospital Mortality Hospitals Human Hypotension Image Immune response Impairment Infection Intervention Liquid substance Low Cardiac Output MAPK8 gene Measurement Mechanical ventilation Mediating Monitor Monoclonal Antibodies Mus Muscle Cells Myocardial Myocardial dysfunction N-terminal Organ Organ failure Pathway interactions Patients Peptide Signal Sequences Performance Perfusion Phase Phosphotransferases Physiological Plasma Production Prognosis Refractory Reporting Resolution Resuscitation Role Sepsis Severities Severity of illness Signal Pathway Signal Transduction Source Stress Supportive care Therapeutic Time Tissues Up-Regulation Vasoconstrictor Agents Vasodilation Ventricular base clinical application design effective therapy heart function heart output disorder high risk hypoperfusion improved insight mortality neutralizing monoclonal antibodies novel novel strategies novel therapeutic intervention patient biomarkers preclinical study pressure public health relevance response septic septic patients targeted treatment therapy development translational impact treatment duration treatment guidelines treatment strategy

项目摘要

Modified Project Summary/Abstract Section Sepsis is the body’s overwhelming immune response to infection that leads to organ failure and death. Refractory hypotension despite administration of vasopressors and fluid resuscitation is the most severe consequence of sepsis with a ~50% in-hospital mortality rate. Currently, there are no targeted therapies to treat sepsis. Existing treatment guidelines focus on source control and supportive care, including early administration of antibiotics and fluid resuscitation. Thus, novel genes and pathways that are involved in the pathophysiology of sepsis are actively sought with the goal to identify new targets that may offer novel therapeutic approaches. Cardiac dysfunction and hypotension in sepsis are associated with poor prognosis and increased mortality. Elevated circulating levels of B-type natriuretic peptide (BNP) correlate with myocardial stress in sepsis, as well as in other types of heart failure. Our data identified a signaling pathway that increased BNP production leads to lower cardiac output. Our previous studies and new data show that cardiac JNK activation, which we have shown to be involved in sepsis pathophysiology, increases BNP expression in septic mice. Our new data show that JNK inhibition increases blood pressure and tissue perfusion in septic mice and this is associated with lower plasma BNP levels. Thus, our central hypothesis is that inhibition of circulating BNP will alleviate septic hypotension and improve survival. To address our hypothesis we have designed the following specific aim: Aim 1 - To assess the role of BNP in reducing CO and promoting hypotension in septic mice and patients. In summary, our goal is to elucidate the role of BNP in the pathophysiology of septic hypotension and explore the therapeutic potential of treatment strategies aimed at regulating BNP expression or neutralizing circulating BNP. Simultaneously, we will pursue clinical studies to evaluate the translational impact of our findings. Thus, we anticipate our findings to constitute the basis for designing future clinical applications aiming to alleviate septic hypotension and organ hypo-perfusion.

修改的项目摘要/摘要部分