Improving treatment personalization for pulmonary hypertension associated with diastolic heart failure

改善舒张性心力衰竭相关肺动脉高压的治疗个体化

• 批准号: 9039103
• 负责人: Julio David Duarte
• 金额: $ 17.69万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9039103
• 关键词: Advisory Committees; Anti-Inflammatory Agents; Anti-inflammatory; Area; Award; Bioinformatics; Blood Vessels; Cardiovascular system; Categories; Chicago; Clinical; Clinical Sciences; Clinical Trials; Collaborations; Complement; Data; Data Analyses; Development; Diastolic heart failure; Disease; EFRAC; Effectiveness; Ensure; Environment; Enzymes; Equipment; Event; FDA approved; Functional disorder; Future; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genome; Genomics; Goals; Grant; Guidelines; Health; Heart failure; Human; Human Genetics; Human Resources; Hyperplasia; Illinois; Inflammation; Institutes; Knowledge; Laboratories; Left; Literature; Lung; Maps; Mentors; Mentorship; Mission; NOS3 gene; Nitric Oxide Synthase; Oral; Outcome; Patients; Pattern; Peripheral Blood Mononuclear Cell; Pharmacogenetics; Pharmacogenomics; Pharmacy facility; Positioning Attribute; Property; Pulmonary Hypertension; Quantitative Trait Loci; Recording of previous events; Research; Research Training; Resources; Risk; Severities; Systemic hypertension; Techniques; Testing; Therapeutic; Time; Training; Translational Research; Treatment Efficacy; Universities; Vasodilation; Vasodilator Agents; Ventricular; Work; base; biomedical informatics; cardiovascular pharmacology; cardiovascular risk factor; career; career development; early-career faculty; evidence base; expectation; experience; functional status; genome-wide; genomic signature; hemodynamics; improved; innovation; insight; interest; meetings; mortality; novel; novel strategies; patient population; personalized medicine; pleiotropism; pressure; prevent; research and development; response; responsible research conduct; skills; small molecule therapeutics; success; therapy development; vasoconstriction

 DESCRIPTION (provided by applicant): PROJECT SUMMARY Clinical trials suggest that nebivolol reduces the risk of cardiovascular events and improves hemodynamics in patients with heart failure with preserved ejection fraction (HFpEF), but its efficacy in patients with pulmonary hypertension (PH) and HFpEF is unknown. The Candidate's long-term goal is to develop an independent research career in translational pharmacogenomics, using novel analytical techniques to improve the treatment of PH through increased personalization of therapy. The objective for this proposal is to evaluate the therapeutic efficacy and associated genomic underpinnings of nebivolol response in patients with PH associated with HFpEF. The central hypothesis is that nebivolol will decrease PH severity in patients with HFpEF, and this response can be predicted by a genomic signature, which corresponds to functional genetic polymorphisms. The rationale for the proposed research is that a genome-based understanding of the therapeutic efficacy of nebivolol for HFpEF-associated PH is likely to contribute to a framework whereby new approaches for treatment can ultimately be developed, while at the same time, helping to establish the Candidate's independence as a translational pharmacogeneticist. To test the central hypothesis and accomplish the objective for this application, the Candidate will pursue the following two specific aims: 1) Evaluate the therapeutic efficacy of nebivolol for PH associated with HFpEF; and 2) Determine genomic underpinnings of nebivolol responsiveness in patients with PH associated with HFpEF. Under the first aim, the primary approach will entail a proof of principle clinical trial, where hemodynamics will be tested before and after four months of daily oral nebivolol treatment. For the second aim, the approach will involve a genome-wide microarray expression analysis, comparing expression patterns with hemodynamic response to nebivolol, as well as a cis-eQTL analysis to correlate nearby polymorphisms to the genes of interest. The proposed research is potentially innovative because it departs from the status quo by focusing on a β-blocker with potentially beneficial pleiotropic effects, nebivolol, for treatment of the acual PH. In addition, the Candidate will focus on identifying a genomic signature of nebivolol response, thus providing data for further personalization of nebivolol therapy. The proposed research is significant because it is expected to contribute meaningfully to the future development of treatments for a disease category that currently has no established treatments. Ultimately, the results from this project are expected to have an important positive impact in that they will provide important proof of principle for the continued development and future clinical trials of nebivolol as a novel approach for treatment of PH associated with HFpEF. In order to attain his long-term goal and the objective for this proposal, the Candidate will require training n clinical trial execution, genome-wide expression analyses, and bioinformatics. Such training, which complements existing expertise in cardiovascular pharmacogenetics and clinical pharmacy, will be achieved through a combination of highly focused coursework, significant hands-on research experience, and active mentored training. The Candidate's mentoring team possesses all the necessary knowledge and skills, including a history of successfully training early-career faculty, for success. Dr. Roberto Machado, Primary Mentor, offers expertise in translational pulmonary research, particularly in PH. Specifically, his research focuses on genomic characterization of pulmonary endothelial function in patients with PH and development of small molecule therapeutics. He is a past K awardee and currently is PI of an R01 grant in the area of the Candidate's project. Dr. Julie Johnson, Primary Mentor, provides expertise in cardiovascular pharmacology and pharmacogenomics. She is currently PI of two U01 and one R01 grants. Neil Bahroos, an expert in biomedical informatics provides necessary expertise in bioinformatics and data analysis. Apart from the three primary mentors, the Candidate has also created an Interdisciplinary Advisory Committee, which will include the primary mentors, but also other advisers with specific expertise to complement those of the mentors. The Advisory Committee will meet quarterly to assess the Candidate's progress, and provide guidance for future research pursuits, as well as professional development and training in the responsible conduct of research. The environment at the University of Illinois at Chicago (UIC) is an ideal setting for the Candidate to acquire research independence in the area of pulmonary pharmacogenomics. In particular, UIC groups such as the Institute for Human Genetics and Center for Clinical and Translational Sciences provide excellent resources for collaboration and career development. Additionally, UIC core laboratories have the necessary state-of-the-art equipment and expertise needed to assist the Candidate in the proposed genomic studies. Importantly, the institutional signing official, Dr. Jerry Bauman, commits all necessary university equipment, facilities, and resources to the Candidate and his career development during the period of the award. This includes a commitment of at least 75% of the Candidate's time for research career development. In summary, the Candidate's demonstrated previous training and experience, innovative research plan, high-quality training plan, outstanding mentorship team, and supportive research environment foretell success in acquiring research independence under the proposed award.

 描述（由申请人提供）： 项目摘要临床试验表明，奈比沃尔降低心血管事件的风险，并改善心力衰竭和保留的射血分数（HFPEF）患者的血液动力学，但其在肺动脉高压（pH）和HFPEF患者中的有效性尚不清楚。候选人的长期目标是利用新颖的分析技术在转化药物基因组学方面发展独立的研究职业，通过增加的治疗个性化来改善pH的治疗。该提案的目的是评估与HFPEF相关的pH患者中奈比沃尔反应的治疗效率和相关的基因组基础。中心假设是，奈比洛尔（Nebivolol）将降低HFPEF患者的pH严重程度，并且可以通过基因组信号来预测这种反应，该基因组信号对应于功能性遗传多态性。拟议的研究的基本原理是，基于基因组对HFPEF相关pH的奈比沃醇的治疗效率的理解很可能有助于一个框架，最终可以开发新的治疗方法，同时有助于确立候选人作为翻译药遗传学家的独立性。为了测试中心假设并实现了本应用的目标，候选人将追求以下两个具体目的：1）评估Nebivolol对HFPEF相关的Nebivolol的治疗效率； 2）确定与HFPEF相关的pH患者中烯比旋酚反应性的基因组基础。在第一个目标下，主要方法将需要进行原则临床试验的证明，在该试验中，将在每天口服nebivolol治疗四个月之前和之后对血液动力学进行测试。为了第二个目标，该方法将涉及全基因组微阵列表达分析，将表达模式与血液动力学反应与奈比沃洛尔进行比较，以及顺式EQTL分析，以将附近的多态性与感兴趣基因相关联。提出的研究具有创新性，因为它通过专注于具有潜在有益的多效性奈比沃洛尔的β受体阻滞剂来治疗Acual PH。此外，候选人将专注于确定奈比沃尔反应的基因组特征，从而提供数据以进一步个性化奈比沃尔治疗。拟议的研究很重要，因为它有望为目前尚无既定治疗的疾病类别的未来治疗方法做出有意义的贡献。最终，该项目的结果有望产生重要的积极影响 他们将为尼比沃洛的持续发展和未来的临床试验提供重要的原理证明，作为一种新型治疗与HFPEF相关的pH治疗方法。为了实现他的长期目标和该提案的目标，候选人将需要培训n临床试验执行，全基因组表达分析和生物信息学。这种培训将通过高度专注的课程，重要的动手研究经验以及积极的指导培训来完成心血管药物遗传学和临床药房的现有专业知识。候选人的指导团队拥有所有必要的知识和技能，包括成功培训早期职业教师的历史。主要导师Roberto Machado博士在翻译肺部研究方面提供了专业知识，尤其是在PH中。具体而言，他的研究重点是pH患者的肺部内皮功能的基因组表征和小分子治疗的发育。他是过去的K获奖者，目前是候选人项目领域的R01赠款的PI。主要导师朱莉·约翰逊（Julie Johnson）博士提供心血管药理学和药物基因组学方面的专业知识。她目前是两个U01和一项R01赠款的PI。生物医学信息专家尼尔·巴鲁斯（Neil Bahroos）在生物信息学和数据分析方面提供了必要的专业知识。除了三位主要导师外，候选人还成立了一个跨学科咨询委员会，其中包括主要导师，还有其他具有特定专业知识的顾问来补充导师的顾问。咨询委员会将每季度开会，以评估候选人的进度，并为未来的研究追求以及负责任的研究进行专业发展和培训提供指导。伊利诺伊大学芝加哥大学（UIC）的环境是候选人获得肺病学领域研究独立性的理想场所。特别是，诸如人类遗传学研究所以及临床和转化科学中心等UIC团体为合作和职业发展提供了出色的资源。此外，UIC核心实验室还具有必要的最新设备和专业知识，以协助候选人进行拟议的基因组研究。重要的是，机构签署官员杰里·鲍曼（Jerry Bauman）博士在奖项期间向候选人及其职业发展提供了所有必要的大学设备，设施和资源。这包括至少有75％的候选人时间进行研究职业发展的承诺。总而言之，候选人展示了以前的培训和经验，创新研究计划，高质量的培训计划，出色的心态团队以及支持性研究环境，预示了根据拟议奖项获得研究独立性的成功。