Improving treatment personalization for pulmonary hypertension associated with diastolic heart failure

 描述(由申请人提供)： 项目摘要临床试验表明，奈比洛尔可降低射血分数(HFpEF)保留的心力衰竭患者发生心血管事件的风险并改善血流动力学，但其对肺动脉高压(PH)和HFpEF患者的疗效尚不清楚。候选人的长期目标是在翻译药物基因组学方面发展独立的研究生涯，使用新的分析技术通过增加治疗的个性化来改进PH的治疗。这项建议的目的是评估奈比洛尔对PH合并HFpEF患者的治疗效果和相关的基因组基础。中心假设是奈比洛尔将降低HFpEF患者的PH严重程度，这种反应可以通过基因组签名来预测，这对应于功能性遗传多态。拟议研究的理由是，基于基因组的对奈比洛尔治疗HFpEF相关PH的疗效的理解可能有助于建立一个框架，最终可以开发新的治疗方法，同时帮助建立候选人作为翻译药物遗传学家的独立性。为了验证中心假设并实现这一应用的目标，候选人将追求以下两个具体目标：1)评估奈比洛尔对与HFpEF相关的PH的疗效；以及2)确定与HFpEF相关的PH患者对奈比洛尔反应的基因组基础。根据第一个目标，主要方法将需要一项原则证明临床试验，在每日口服奈比洛尔治疗四个月之前和之后进行血流动力学测试。对于第二个目标，该方法将涉及全基因组微阵列表达分析，将表达模式与奈比洛尔的血流动力学反应进行比较，以及顺式eQTL分析，以将邻近的多态与感兴趣的基因相关联。这项拟议的研究具有潜在的创新性，因为它偏离了现状，专注于一种具有潜在有益的多效性作用的β阻滞剂奈比洛尔，用于治疗急性PH。此外，候选人将专注于识别奈比洛尔反应的基因组签名，从而为奈比洛尔治疗的进一步个性化提供数据。这项拟议的研究意义重大，因为预计它将对目前尚无既定治疗方法的疾病类别的治疗方法的未来发展做出有意义的贡献。最终，这个项目的结果预计将在以下方面产生重要的积极影响 这将为奈比洛尔的继续开发和未来的临床试验提供重要的原则证据，奈比洛尔是一种治疗高血压合并HFpEF的新方法。为了实现他的长期目标和这项提议的目标，候选人将需要在临床试验执行、全基因组表达分析和生物信息学方面的培训。这种培训是对心血管药物遗传学和临床药学现有专业知识的补充，将通过高度专注的课程作业、重要的实践研究经验和积极的指导培训相结合的方式实现。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。罗伯托·马查多博士，初级导师，提供翻译肺研究方面的专业知识，特别是在PH方面。具体地说，他的研究重点是肺高压患者肺内皮细胞功能的基因组特征以及小分子疗法的开发。他是过去的K奖获得者，目前是候选人项目领域的R01补助金的PI。首席导师朱莉·约翰逊博士提供心血管药理学和药物基因组学方面的专业知识。她目前是两名U01和一名R01奖助金的PI。生物医学信息学专家尼尔·巴鲁斯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，候选人还创建了一个跨学科咨询委员会，该委员会将包括主要导师，但也有其他具有特定专业知识的顾问，以补充导师的专业知识。咨询委员会将每季度举行一次会议，评估候选人的进展情况，并为今后的研究工作以及负责任地开展研究的专业发展和培训提供指导。伊利诺伊大学芝加哥分校(UIC)的环境是候选人在肺部药物基因组学领域获得研究独立性的理想环境。特别是，UIC组织，如人类遗传学研究所和临床与转化科学中心，为合作和职业发展提供了极好的资源。此外，UIC核心实验室拥有必要的最先进的设备和专业知识，以协助候选人进行拟议的基因组研究。重要的是，机构签约官员曾傑瑞·鲍曼博士承诺在获奖期间为候选人及其职业发展提供所有必要的大学设备、设施和资源。这包括应聘者至少75%的时间用于研究职业发展。综上所述，候选人以往的培训和经验、创新的研究计划、高质量的培训计划、杰出的导师团队和支持性的研究环境预示着在拟议奖项下获得研究独立性的成功。

 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.