HL146818-Uric Acid, Klotho and Salt Sensitivity in Young Adults Born Preterm

HL146818-早产青年的尿酸、Klotho 和盐敏感性

基本信息

批准号：
10175748
负责人：
MARK C CHAPPELL
金额：
$ 5.79万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
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：
2019-08-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10175748
关键词：
Address Admission activity Adult American American Heart Association Angiotensinogen Angiotensins Animals Antibodies Applications Grants Appointment Area Award Biochemical Biological Assay Biological Markers Biology Biomedical Research Biometry Birth Rate Blood Pressure Cardiology Cardiovascular Diseases Cardiovascular system Career Choice Cause of Death Cell physiology Cells Characteristics Clinical Clinical Sciences Co-Immunoprecipitations Collaborations Committee Members Communication Complement Computational Biology Critiques Data Data Analyses Development Doctor of Philosophy Ensure Enzyme-Linked Immunosorbent Assay Ethics Evaluation Event Exhibits Exposure to Extramural Activities Faculty Feedback Fellowship Foundations Frequencies Functional disorder Funding Future Goals Grant Graph Health Personnel Human Hypertension Inactive Renin Incidence Individual Infant Inflammation Inflammatory International Internships Journals Kidney Knowledge Laboratories Laboratory Research Lead Learning Life Link Literature Manuscripts Mass Spectrum Analysis Measures Medical Mentors Messenger RNA Metabolism Methods Microscopy Modeling Molecular Molecular Medicine Oral Organ Outcome Paper Pathology Pathway interactions Patients Peer Review Peptides Performance Pharmacologic Substance Pharmacology Phosphoproteins Physiology Postdoctoral Fellow Premature Birth Prevention Prevention strategy Process Proteins Proximal Kidney Tubules Publications Publishing Recording of previous events Regulation Renal tubule structure Renin Renin-Angiotensin System Reproducibility Research Research Activity Research Personnel Research Project Grants Research Proposals Research Training Resources Rest Risk Risk Factors Role Schools Scientist Series Signal Pathway Signal Transduction Slide Sodium Chloride Solid Students System TLR4 gene Techniques Time TimeLine Training Training Programs United States National Institutes of Health Universities Up-Regulation Update Uric Acid Western Blotting Work Writing analytical method anti aging base blood pressure regulation cardiovascular risk factor career career development cohort cytokine data integration emerging adult experience experimental study falls fetal fetal programming graduate student high risk high salt diet improved indexing innovation insight interest journal article lectures meetings member mid-career faculty novel therapeutics peer pre-doctoral preclinical study premature professor programs prorenin receptor response salt intake salt sensitive salt sensitive hypertension skill acquisition skills success summer research symposium treatment strategy undergraduate student university student uptake urinary young adult

项目摘要

ABSTRACT Hypertension is the leading risk factor for cardiovascular disease, is highly prevalent with high lifetime cumulative incidence rates, and is the leading cause of death compared to any other risk factor. Premature birth is an emerging and important risk factor for hypertension and cardiovascular disease, as both preterm birth rates and infant survival increase worldwide. Hypertension and cardiovascular disease begin in early adulthood in individuals born prematurely, but the reasons – especially in regard to the role of preterm birth – are unknown. An improved understanding of why hypertension and cardiovascular disease occur in early adulthood in individuals born preterm will enable the development of prevention and treatment strategies to mitigate the burden of cardiovascular disease. Salt sensitivity of blood pressure (SSBP; the change in blood pressure in response to a change in salt intake) is an emerging risk factor for hypertension and cardiovascular disease. However, little is known about the pathophysiology of SSBP, which limits its treatment and prevention. Individuals born preterm may be at higher risk for SSBP, but this too is unknown. Uric acid, which is higher in those born preterm due to altered uric acid metabolism, has been linked to development of SSBP in preclinical studies, but this concept has not been investigated in human trials. Uric acid may lead to SSBP via changes in klotho and the renin-angiotensin system, notably changes in the soluble prorenin receptor (sPRR) in the renal proximal tubules which has been linked to upregulation of Na+ transporters that may contribute to salt-sensitivity. Thus, the proposed study will determine the role of sPRR in this patient cohort and in human proximal tubule cells by the candidate. The diversity supplement serves as a robust and comprehensive training plan for the candidate graduate student includes the research plan involving the assessment of the sPRR in term and preterm adults maintained on a high salt diet, the role of Uric Acid on the regulation of sPRR in preterm salt-sensitive patients and the regulation of the sPRR in human proximal tubules and the functional and signaling characteristics of the sPRR. The mentoring team for the candidate is led by experienced and senior investigators with extensive experience in the preterm and term cohort, the influence of programing events on hypertension and internationally recognized expertise in the renin-angiotensin system and renal models of hypertensive disease. In addition to providing a comprehensive training plain that will ensure a strong foundation and pathway of the candidate to an independent investigator, the proposed research will establish the role of sPRR among individuals born preterm, thus providing evidence for the mechanisms behind the increased risk of hypertension and cardiovascular disease in individuals born prematurely.

抽象的高血压是心血管疾病的主要危险因素，其患病率很高，寿命较长累积发病率，与任何其他危险因素相比，是导致过早死亡的主要原因。出生是高血压和心血管疾病的一个新兴的重要危险因素，因为早产全世界的出生率和婴儿存活率均有所提高，高血压和心血管疾病很早就开始出现。早产个体的成年期，但其原因——尤其是早产的作用 – 对高血压和心血管疾病发生的原因尚不清楚。早产儿的成年早期将有助于预防和治疗的发展减轻心血管疾病负担的策略。血压盐敏感性（SSBP；盐摄入量变化引起的血压变化）是高血压的一个新兴危险因素然而，人们对 SSBP 的病理生理学知之甚少，这限制了它的发展。治疗和预防早产儿患 SSBP 的风险可能较高，但这也是未知的。由于尿酸代谢改变，早产儿的尿酸较高，这与 SSBP 在临床前研究中得到了发展，但这一概念尚未在人体试验中得到研究。酸可能通过 klotho 和肾素-血管紧张素系统的变化导致 SSBP，可溶性的显着变化肾近曲小管中的肾素原受体 (sPRR) 与 Na+ 的上调有关因此，拟议的研究将确定 sPRR 的作用。在该患者队列和候选者的人类近端小管细胞中，多样性起到了补充作用。作为候选研究生的强大而全面的培训计划，包括研究计划对维持高盐饮食的足月和早产成人的 sPRR 进行评估，尿酸对早产盐敏感患者 sPRR 的调节及对早产儿 sPRR 的调节人类近曲小管以及 sPRR 的功能和信号特征指导团队。候选人由在早产儿方面拥有丰富经验的经验丰富的高级调查员领导和学期队列、规划活动对高血压的影响以及国际公认的专业知识在肾素-血管紧张素系统和高血压疾病的肾脏模型中。全面的培训平原，将确保候选人打下坚实的基础和途径独立研究者，拟议的研究将确定 sPRR 在出生个体中的作用早产，从而为高血压和高血压风险增加背后的机制提供证据早产儿的心血管疾病。