Advanced CV imaging and immunophenotyping to study coronary vascular health in psoriasis

项目总结/摘要 银屑病与心血管疾病（CVD）高度相关，包括心肌梗死（MI）、心力衰竭和 CV死亡率。这些患者中CV风险因素的患病率增加只是部分原因 增加临床风险。虽然全身炎症被认为是发病的关键介质， 随着这些心脏代谢异常的进展，银屑病疾病赋予的额外CV风险仍然存在 替补演员我们将使用新的多模态心脏成像来量化血管健康的异常， 心脏结构和功能，并评估与细胞免疫表型的关联。中央 本研究的假设是用tildrakizumab（一种FDA批准的治疗银屑病的药物）减轻炎症 抑制炎症的IL-23和Th 17途径，将定量改善心肌血流量， 患者6个月内通过正电子发射断层扫描（PET）测量的冠脉血流储备（CFR） 中度至重度银屑病和心血管风险增加。这样做，改善冠状动脉 血管反应性、内皮功能和组织灌注可能对心肌力学具有有益作用， 最后是症状和预后我们建议使用两种最先进的技术，定量 灌注PET成像和通过单细胞分析的细胞免疫表型[单细胞RNA-seq，细胞 外周血单核细胞的转录组和表位索引（CITE）-seq]，结合 超声心动图在具体目标1中，我们将评估tildrakizumab治疗是否（1）改善冠状动脉粥样硬化性心脏病（CHD）， 血管功能的基础上CFR，（2）改善心肌力学，（3）是否这种功能的改善 将与治疗6个月后CFR的变化相关。在具体目标2中，我们将评估 细胞免疫表型与冠状动脉血管功能不全及心肌梗死的关系 力学，在基线和tildrakizumab治疗6个月后。本提案的总体目标是 是使用已经作为常规临床护理的一部分可用的生理成像技术， 免疫分型研究银屑病疾病和炎症与冠状动脉血管的联系机制 健康和心脏结构和功能。本研究将解决未满足和需要的临床翻译， 牛皮癣疾病本研究将在全面职业发展的背景下进行 该计划旨在为候选人提供CV医学和CV培训的早期职业研究者 成像，与所需的技能，成为一个独立的医生，科学家在CV医学。她的长期 职业目标是成为一名独立的科学研究者，将免疫学与心血管成像相结合 更好地定义全身炎症在心血管病理生理学中的作用，并最终为未来的研究提供信息。 治疗试验一个杰出的指导团队和咨询委员会的既定科学家在该领域 CV医学，CV成像，流变学，皮肤病学，免疫学和细胞生物学将指导 候选人在获奖期间向科学独立过渡。

Project Summary/Abstract Psoriasis is highly linked to cardiovascular disease (CVD), including myocardial infarction (MI), heart failure and CV mortality. An increased prevalence of CV risk factors in these patients only partially accounts for this enhanced clinical risk. Although systemic inflammation is thought to be a key mediator of the onset and progression of these cardiometabolic abnormalities, the excess CV risk conferred by psoriatic disease remains understudied. We will use novel multi-modality cardiac imaging to quantify abnormalities in vascular health, and cardiac structure and function and assess the association with cellular immunophenotype. The central hypothesis of this study is that reducing inflammation with tildrakizumab, an FDA approved therapy for psoriasis that inhibits the IL-23 and Th17 pathway of inflammation, will quantitatively improve myocardial blood flow and coronary flow reserve (CFR) as measured by positron emission tomography (PET) over 6 months in patients with moderate-severe psoriasis disease and enhanced CV risk. In so doing, improvement in coronary vasoreactivity, endothelial function, and tissue perfusion may have beneficial effects on myocardial mechanics, and ultimately, symptoms and prognosis. We propose to use two state-of-the-art techniques, quantitative perfusion PET imaging and cellular immunophenotyping by single cell analysis [single cell RNA-seq, cellular indexing of transcriptomes and epitopes (CITE)-seq] of peripheral blood mononuclear cells, combined with echocardiography. In Specific Aim 1, we will evaluate whether tildrakizumab therapy will (1) improve coronary vascular function based on CFR, (2) improve myocardial mechanics, and (3) whether this functional improvement will be correlated with the change in CFR after 6 months of treatment. In Specific Aim 2, we will evaluate the relationship between cellular immunophenotype and coronary vasomotor dysfunction and myocardial mechanics, at baseline and after therapy with tildrakizumab for 6 months. The overarching goal of this proposal is to use physiologic imaging techniques already available as part of routine clinical care, and novel cellular immunophenotyping to investigate mechanisms linking psoriatic disease and inflammation to coronary vascular health and cardiac structure and function. This study will address an unmet and needed clinical translation in psoriatic disease. This research will be accomplished in the setting of a comprehensive career development program designed to provide the candidate, an early career investigator with training in CV medicine and CV imaging, with the skills needed to become an independent physician-scientist in CV medicine. Her long-term career goal is to be an independent scientific investigator, integrating immunology with cardiovascular imaging to better define the role of systemic inflammation in cardiovascular pathophysiology, and ultimately inform future therapeutic trials. An outstanding mentoring team and advisory committee of established scientists in the fields of CV medicine, CV imaging, Rheumatology, Dermatology, Immunology, and cellular biology will guide the candidate in her transition to scientific independence over the course of the award period.