Improving treatment personalization for pulmonary hypertension associated with diastolic heart failure

 描述（由申请人提供）： 临床试验表明，奈必洛尔可降低射血分数保留性心力衰竭（HFpEF）患者的心血管事件风险并改善血流动力学，但其在肺动脉高压（PH）和HFpEF患者中的疗效尚不清楚。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事业，使用新的分析技术通过增加个性化治疗来改善PH的治疗。本提案的目的是评价奈必洛尔在HFpEF相关PH患者中的疗效和相关基因组基础。中心假设是奈必洛尔将降低HFpEF患者的PH严重程度，并且这种反应可以通过基因组特征预测，其对应于功能性遗传多态性。拟议研究的基本原理是，基于基因组对奈必洛尔治疗HFpEF相关PH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，同时有助于建立候选人作为翻译药物遗传学家的独立性。为了检验中心假设并实现本申请的目的，候选人将追求以下两个特定目标：1）评价奈必洛尔治疗HFpEF相关PH的疗效; 2）确定奈必洛尔在HFpEF相关PH患者中反应性的基因组基础。在第一个目标下，主要方法将需要一个原理性临床试验的证明，在每天口服奈必洛尔治疗四个月之前和之后将测试血液动力学。对于第二个目标，该方法将涉及全基因组微阵列表达分析，比较表达模式与奈必洛尔的血流动力学反应，以及顺式eQTL分析，以将附近的多态性与感兴趣的基因相关联。拟议的研究具有潜在的创新性，因为它偏离了现状，专注于具有潜在有益多效性作用的β受体阻滞剂奈必洛尔，用于治疗急性PH。此外，候选人将专注于确定奈必洛尔反应的基因组特征，从而为奈必洛尔治疗的进一步个性化提供数据。这项拟议中的研究意义重大，因为它有望为目前尚未确定治疗方法的疾病类别的未来治疗发展做出有意义的贡献。最终，该项目的成果预计将产生重要的积极影响， 它们将为奈必洛尔作为治疗HFpEF相关PH的新方法的持续开发和未来临床试验提供重要的原则证据。为了实现其长期目标和本提案的目标，候选人将需要接受临床试验执行、全基因组表达分析和生物信息学方面的培训。这种培训补充了心血管药物遗传学和临床药学的现有专业知识，将通过高度集中的课程作业，重要的实践研究经验和积极的指导培训相结合来实现。候选人的辅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，以取得成功。Roberto马查多博士，主要导师，提供转化肺研究的专业知识，特别是在PH。具体来说，他的研究重点是PH患者肺内皮功能的基因组表征和小分子疗法的开发。他是一个过去的K获奖者，目前是在候选人的项目领域的R 01赠款PI。Julie约翰逊博士，主要导师，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U 01和一个R 01赠款的PI。Neil Bahroos是生物医学信息学专家，提供生物信息学和数据分析方面的必要专业知识。除了三名主要导师外，候选人还设立了一个跨学科咨询委员会，其中包括主要导师，但也包括具有具体专门知识的其他顾问，以补充导师的专门知识。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方面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集团，如人类遗传学研究所和临床和转化科学中心，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，该机构的签约官员，博士杰里鲍曼，承诺所有必要的大学设备，设施和资源，候选人和他的职业发展在获奖期间。这包括候选人至少75%的时间用于研究职业发展。总而言之，候选人所展示的先前培训和经验，创新的研究计划，高质量的培训计划，优秀的导师团队和支持性的研究环境预示着在拟议的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.