A Novel Biomarker of Mineralocorticoid Receptor Activation

盐皮质激素受体激活的新型生物标志物

• 批准号: 9897582
• 负责人: James Brian Byrd
• 金额: $ 19.44万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9897582
• 关键词: 20 year old; Acute; Adult; Adverse effects; Affect; Aldosterone; American; Amiloride; Angioneurotic Edema; Angiotensin-Converting Enzyme Inhibitors; Animal Model; Antihypertensive Agents; Attention; Award; Bioinformatics; Biological; Biological Assay; Biological Markers; Biology; Blood Pressure; Cardiovascular Diseases; Cardiovascular system; Cells; Cessation of life; Clinical; Clinical Management; Clinical Pharmacology; Clinical Trials; Colorado; Data; Development; Diabetes Mellitus; Diagnosis; Distal; Doctor of Philosophy; EFRAC; Endocrinology; Enrollment; Environment; Epithelial Cells; Excretory function; Faculty; Fellowship; Functional disorder; Funding Mechanisms; Genes; Genetic Transcription; Glucocorticoids; Goals; Health; Health Personnel; Heart failure; Hour; Human; Hyperaldosteronism; Hypertension; Institutes; Internal Medicine; Italy; Kidney; Knowledge; Laboratories; Leucine Zippers; Master of Science; Medicine; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Messenger RNA; Michigan; MicroRNAs; Mineralocorticoid Receptor; Mineralocorticoids; Nephrons; Obesity; Participant; Patient Care; Patients; Pattern; Pharmaceutical Preparations; Physiology; Placebos; Plasma; Population; Positioning Attribute; Potassium; Proteins; Public Health; Randomized; Randomized Controlled Trials; Receptor Activation; Renin; Renin-Angiotensin-Aldosterone System; Research; Research Personnel; Research Training; Residencies; Resistance; Resistant Hypertension; Risk; Sampling; Science; Seminal; Serum; Sgk protein; Societies; Sodium; Sodium-Restricted Diet; Specialist; Spironolactone; Surface; Time; Training; Transcript; Tubular formation; Uncertain Risk; United States; United States National Institutes of Health; Universities; Validation; Water; Work; adrenal hypertension; aldosterone hypertension; base; biomarker development; biomarker discovery; biomarker evaluation; cardiovascular disorder risk; clinical application; clinical biomarkers; clinical investigation; epithelial Na+ channel; eplerenone; exosome; experience; healthy volunteer; hypertension control; hypertension treatment; improved; individualized medicine; interest; low renin hypertension; member; microvesicles; novel marker; patient oriented; patient oriented research; predicting response; preservation; public health relevance; randomized placebo controlled trial; randomized trial; recruit; response; risk benefit ratio; screening; skills; statistics; tool; transcriptome; transcriptomics; treatment strategy; urinary

 DESCRIPTION (provided by applicant): The candidate for this K23 award is dedicated to becoming an independent patient-oriented investigator with expertise in biomarker development and evaluation, clinical trials, and mineralocorticoid-induced hypertension. The proposed award will allow the candidate to accomplish this goal while evaluating a novel biomarker of mineralocorticoid receptor (MR) activation for use in tailored antihypertensive therapy. Candidate. The candidate is well prepared for this award because of his prior training. After internal medicine residency, he investigated the pathophysiology of angiotensin-converting enzyme inhibitor (ACEi)-associated angioedema in Vanderbilt University's Division of Clinical Pharmacology. While receiving excellent training in the clinical management of hypertension, he enrolled study participants and assayed their samples in the laboratory, igniting a passion for patient-oriented research. He earned Vanderbilt's Master of Science in Clinical Investigation degree. In addition, he helped conduct a randomized trial to treat acute ACEi-associated angioedema while developing an animal model recapitulating important aspects of this rare, but potentially fatal problem. Based upon a growing interest in hypertension and cardiovascular disease, he completed a clinical cardiovascular medicine fellowship at the University of Colorado, where he was elected the Gilbert Blount Endowed Research Fellow. During this fellowship, he maintained a research focus on hypertension. Upon recruitment to the University of Michigan, he has turned his attention to a problem of major public health importance: tailored treatment of patients with hypertension. The candidate is a cardiologist, and American Society of Hypertension-Certified Hypertension Specialist. He is well positioned to become a leader in patient-oriented hypertension research. His background in patient- oriented research has prepared him to become an expert in the clinical investigation of mineralocorticoid-induced hypertension. His research independence will be achieved through three Training Objectives: (1) comprehensive laboratory and statistical training relevant to biomarkers of human MR activation, (2) in-depth training in endocrine hypertension and aldosterone's effects on human physiology, and (3) experience directing a randomized controlled trial (RCT). Environment. The proposed research and training will take place at the University of Michigan, which has a proud legacy of seminal mineralocorticoid research. The candidate is a faculty member in Cardiovascular Medicine, which has close collaborative ties with the Division of Metabolism, Endocrinology, and Diabetes; the Department of Physiology; and the University of Michigan's CTSA, the Michigan Institute for Clinical and Health Research. The proposed work will be completed under close mentorship from Drs. Richard Auchus, MD, PhD and William Rainey, PhD, recognized experts in mineralocorticoid biology, both of whom have mentored K awardees. Robert Brook, MD will guide the candidate in the contemporary conduct of hypertension RCTs. Muneesh Tewari, MD, PhD will train the PI in transcriptomics, completing the mentorship team. Research. The focus of this K23 proposal is hypertension, a condition affecting 33% of the United States' adult population. Hypertension increases the risk of cardiovascular disease and death, and its treatment reduces these risks. Hypertension resistant to treatment is common. Approximately 20% of patients with resistant hypertension have primary aldosteronism, in which inappropriate aldosterone secretion leads to activation of MR. Activation of MR increases the expression of serum/glucocorticoid regulated kinase 1 (SGK1), glucocorticoid-induced leucine zipper, and the amiloride-sensitive epithelial sodium channel (ENaC) in the distal nephron, resulting in sodium and water retention. MR antagonists (MRAs) are predictably effective in the treatment of primary aldosteronism. Beyond primary aldosteronism, MRAs are also an effective antihypertensive treatment in many patients with normal or low circulating levels of aldosterone. However, an uncertain risk-benefit ratio has precluded common use of MRAs for hypertension. No biomarker of MR activation exists, but such a biomarker would permit clinicians to target MRA therapy to appropriate patients and spare other patients unnecessary adverse effects. Preliminary data suggest that mRNA encoding MR-regulated genes is quantifiable in urinary exosomes, 40-120 nm microvesicles shed by cells. The overall scientific objective of this proposal is to evaluate whether mRNA shuttled by urinary exosomes is a clinically useful biomarker of MR activation. Specific Aim 1 (aligns with Training Objective 1): Define biomarkers of MR activation in urinary exosomes in healthy volunteers on high- and low-sodium diet a. Determine the utility of known MR-responsive genes as biomarkers in urinary exosomes b. Use transcriptome analysis to define novel biomarkers of mineralocorticoid excess in urinary exosomes Specific Aim 2 (aligns with Training Objective 2): Determine the utility of MR-responsive transcript abundance in urinary exosome-shuttled for the diagnosis and subtyping of primary aldosteronism Specific Aim 3 (aligns with Training Objective 3): Evaluate urinary exosome-shuttled MR-responsive transcript patterns as predictors of blood pressure response to spironolactone in patients with low-renin hypertension Summary. The proposed K23 award will provide the candidate sufficient protected time and training to become an independent clinical translational hypertension investigator. The research will answer important, tractable questions about exosome-shuttle transcriptional biomarkers for tailoring antihypertensive therapy.

 描述（由申请人提供）：该 K23 奖项的候选人致力于成为一名独立的以患者为导向的研究者，在生物标志物开发和评估、临床试验以及盐皮质激素诱发的高血压方面拥有专业知识。拟议的奖项将使候选人能够实现这一目标。候选者在评估用于定制抗高血压治疗的新型盐皮质激素受体（MR）激活生物标志物时，已为这一目标做好了准备，因为他之前接受过内科住院医师培训。范德比尔特大学临床药理学部的血管紧张素转换酶抑制剂（ACEi）相关血管性水肿的病理生理学在接受高血压临床管理方面的出色培训的同时，他招募了研究参与者并在实验室分析了他们的样本，点燃了对患者的热情。他获得了范德比尔特大学临床研究理学硕士学位，此外，他还帮助开展了一项治疗急性 ACEi 相关血管性水肿的随机试验，同时开发了动物模型。基于对高血压和心血管疾病日益增长的兴趣，他在科罗拉多大学完成了心血管临床医学奖学金，并在该奖学金期间被选为吉尔伯特·布朗特研究员。进入密歇根大学后，他将研究重点转向了一个具有重大公共卫生意义的问题：高血压患者的定制治疗。认证高血压专家。他有能力成为以患者为导向的高血压研究的领导者。他以患者为导向的研究背景使他成为盐皮质激素引起的高血压临床研究的专家。他的研究独立性将通过三个培训目标来实现：（ 1) 与人类 MR 激活生物标志物相关的综合实验室和统计培训，(2) 内分泌高血压和醛固酮对人体生理学影响的深入培训，以及 (3) 指导随机对照试验 (RCT) 的经验。研究和培训将在密歇根大学进行，该大学拥有令人自豪的盐皮质激素研究遗产，该候选人是心血管医学系的教员，该大学与该系的代谢、内分泌和糖尿病部门有着密切的合作关系；生理学系、密歇根大学 CTSA、密歇根临床与健康研究所拟议的工作将在 Richard Auchus 博士和 William Rainey 博士的密切指导下完成。盐皮质激素生物学领域的知名专家 Robert Brook 医学博士将指导候选人进行当代高血压随机对照试验，Muneesh Tewari 医学博士将对 PI 进行转录组学培训，从而完成指导团队的工作。 K23 提案的重点是高血压，这种疾病影响着 33% 的美国成年人口，会增加心血管疾病和死亡的风险，而其治疗可降低这些风险。大约 20% 的顽固性高血压患者患有原发性醛固酮增多症，其中醛固酮分泌不当导致 MR 激活，从而增加血清/糖皮质激素调节激酶 1 (SGK1)、糖皮质激素诱导的亮氨酸拉链的表达。远端肾单位的阿米洛利敏感上皮钠通道 (ENaC)，产生钠和水MR 拮抗剂 (MRA) 预计可有效治疗原发性醛固酮增多症，除原发性醛固酮增多症外，MR 拮抗剂对于许多醛固酮循环水平正常或较低的患者也是一种有效的抗高血压治疗方法。 MRA 治疗高血压的常见用途不存在 MR 激活的生物标志物，但这样的生物标志物将允许将 MRA 治疗靶向适当的患者，并避免其他不必要的患者副作用。初步数据表明，编码 MR 调节基因的 mRNA 在尿外泌体（细胞脱落的 40-120 nm 微泡）中是可定量的。该提案的总体科学目标是评估尿外泌体穿梭的 mRNA 是否是临床上有用的 MR 激活生物标志物。具体目标 1（与培训目标 1 一致）：定义健康志愿者尿外泌体中 MR 激活的生物标志物低钠饮食 a. 确定已知 MR 响应基因作为尿外泌体中生物标志物的效用 b. 使用转录组分析来定义尿外泌体中盐皮质激素过量的新生物标志物 具体目标 2（与培训目标 2 一致）：确定尿外泌体中 MR 响应转录物丰度用于原发性醛固酮增多症的诊​​断和分型具体目标 3（与培训目标 3 一致）：评估尿外泌体穿梭的 MR 反应转录模式作为低肾素高血压患者对螺内酯血压反应的预测因子摘要拟议的 K23 奖项将为候选人提供足够的保护时间和时间。该研究将回答有关外泌体穿梭转录生物标志物的重要且易于处理的问题，以定制抗高血压治疗。

项目成果

Hypertension Hot Potato - Anatomy of the Angiotensin-Receptor Blocker Recalls.

高血压烫手山芋 - 血管紧张素受体阻滞剂召回剖析。

• 发表时间: 2019-04-25
• 作者: Byrd, J Brian;Chertow, Glenn M;Bhalla, Vivek
• 通讯作者: Bhalla, Vivek

Blood pressure, heart rate, and mortality in chronic obstructive pulmonary disease: the SUMMIT trial.

慢性阻塞性肺疾病的血压、心率和死亡率：SUMMIT 试验。

• 发表时间: 2018
• 影响因子: 39.3
• 作者: Byrd, James Brian;Newby, David E;Anderson, Julie A;Calverley, Peter M A;Celli, Bartolome R;Cowans, Nicholas J;Crim, Courtney;Martinez, Fernando J;Vestbo, Jørgen;Yates, Julie;Brook, Robert D;SUMMIT Investigators
• 通讯作者: SUMMIT Investigators

Primary Aldosteronism: New Insights Into its Detection and Cardiac Involvement.

原发性醛固酮增多症：对其检测和心脏参与的新见解。

• 发表时间: 2020
• 作者: Pitt, Bertram;Byrd, James Brian
• 通讯作者: Byrd, James Brian

Testing for Primary Aldosteronism and Mineralocorticoid Receptor Antagonist Use Among U.S. Veterans : A Retrospective Cohort Study.

美国退伍军人中原发性醛固酮增多症和盐皮质激素受体拮抗剂使用情况的测试：一项回顾性队列研究。

• 发表时间: 2021
• 影响因子: 39.2
• 作者: Cohen, Jordana B;Cohen, Debbie L;Herman, Daniel S;Leppert, John T;Byrd, James Brian;Bhalla, Vivek
• 通讯作者: Bhalla, Vivek

Opening Opportunities With Open Data.

通过开放数据打开机会。

• 发表时间: 2018
• 作者: Zheutlin, Alexander R;Byrd, James Brian
• 通讯作者: Byrd, James Brian