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

项目摘要/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 病死率。这些患者中心血管危险因素的增加只能部分解释这一点 增加了临床风险。尽管全身性炎症被认为是发病和死亡的关键介质 在这些心脏代谢异常的进展中，银屑病带来的额外心血管风险仍然存在 未得到充分研究。我们将使用新的多模式心脏成像来量化血管健康中的异常，以及 心脏结构和功能，并评估其与细胞免疫表型的关系。中环 这项研究的假设是，FDA批准的银屑病治疗方法替屈珠单抗可以减少炎症 抑制IL-23和Th17途径的炎症，将定量改善心肌血流量和 6个月以上患者正电子发射断层扫描测定冠状动脉血流储备(CFR) 患有中-重度牛皮癣，心血管风险增加。通过这样做，冠状动脉的改善 血管反应性、内皮功能和组织灌流可能对心肌力学有有利影响， 最后是症状和预后。我们建议使用两种最先进的技术，量化 单细胞分析的灌注PET成像和细胞免疫表型[单细胞RNA序列 外周血单核细胞转录本和表位索引(CITE-SEQ)，与 超声心动图。在特定的目标1中，我们将评估替德拉吉单抗治疗是否将(1)改善冠状动脉 基于CFR的血管功能，(2)改善心肌力学，以及(3)这种功能改善 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运动功能障碍及心肌梗死的关系 治疗前和治疗6个月后的力学指标。这项提案的首要目标是 是使用已经作为常规临床护理的一部分的生理成像技术，以及新的细胞 银屑病和炎症与冠状动脉血管联系机制的免疫表型研究 健康和心脏的结构和功能。这项研究将解决一个未得到满足和需要的临床翻译 牛皮癣。这项研究将在全面职业发展的背景下完成 旨在为应聘者、早期职业调查员提供简历医学和简历培训的计划 具备成为心血管医学领域独立内科医生兼科学家所需的技能。她的长期工作 职业目标是成为一名独立的科学研究员，将免疫学与心血管成像相结合 更好地确定全身炎症在心血管病理生理学中的作用，并最终告知未来 治疗试验。由该领域的知名科学家组成的杰出的指导团队和咨询委员会 心血管医学、心血管成像、风湿病学、皮肤病学、免疫学和细胞生物学将指导 在获奖期内，她在向科学独立的过渡过程中成为了候选人。

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.