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

先进的 CV 成像和免疫表型研究银屑病冠状血管健康

• 批准号: 10459556
• 负责人: Brittany nicole Weber
• 金额: $ 19.19万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10459556
• 关键词: Address; Advisory Committees; Affect; Aftercare; Age; Anti-Inflammatory Agents; Atherosclerosis; Award; Blood Vessels; Blood flow; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cells; Cellular biology; Cessation of life; Clinical; Clinical Trials; Coronary; Coronary Arteriosclerosis; Data; Dermatology; Development; Disease; Echocardiography; Endothelium; Epitopes; Event; Exposure to; FDA approved; Foundations; Functional Imaging; Functional disorder; Funding; Future; Goals; Health; Heart failure; Heterogeneity; High Prevalence; Imaging Techniques; Immune; Immunologist; Immunology; Immunophenotyping; Impairment; Inflammation; Inflammatory; Interleukin-17; Investigation; Left Ventricular Function; Link; Measures; Mechanics; Mediating; Mediator of activation protein; Medicine; Mentors; Methods; Microvascular Dysfunction; Molecular Profiling; Monitor; Morphology; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial dysfunction; Myocardial tissue; Outcome; Pathway interactions; Patients; Perfusion; Peripheral Blood Mononuclear Cell; Physicians; Play; Population; Population Control; Positron-Emission Tomography; Prevalence; Prevention strategy; Prognosis; Program Development; Psoriasis; Psoriatic Arthritis; Relaxation; Research; Research Personnel; Rheumatology; Risk; Risk Factors; Role; Scientist; Severity of illness; Solid; Stress; Structure; Symptoms; Techniques; Testing; Therapeutic Trials; Tissues; Training; Translations; Vascular Diseases; Vasodilator Agents; Vasomotor; base; cardiometabolic risk; cardiometabolism; cardiovascular disorder risk; cardiovascular imaging; cardiovascular risk factor; career; career development; chronic inflammatory skin; clinical care; clinical risk; clinical translation; design; endothelial dysfunction; functional improvement; genetic signature; heart imaging; improved; indexing; insight; interleukin-23; mortality; multimodality; novel; patient population; prevent; response; sex risk; single cell analysis; single-cell RNA sequencing; skills; skin disorder; systemic inflammatory response; transcriptome; transcriptome sequencing

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.

项目概要/摘要 牛皮癣与心血管疾病 (CVD) 高度相关，包括心肌梗塞 (MI)、心力衰竭和 心血管死亡率。这些患者中心血管危险因素患病率的增加只是部分原因 增加临床风险。尽管全身炎症被认为是发病和发生的关键介质 随着这些心脏代谢异常的进展，牛皮癣疾病带来的过度心血管风险仍然存在 待研究。我们将使用新型多模态心脏成像来量化血管健康异常，以及 心脏结构和功能并评估与细胞免疫表型的关联。中央 这项研究的假设是，用 tildrakizumab（FDA 批准的治疗牛皮癣的疗法）减少炎症 抑制IL-23和Th17炎症通路，定量改善心肌血流量， 通过正电子发射断层扫描 (PET) 测量患者 6 个月以上的冠状动脉血流储备 (CFR) 患有中重度银屑病且心血管风险增加。这样做，可以改善冠状动脉 血管反应性、内皮功能和组织灌注可能对心肌力学产生有益的影响， 最后是症状和预后。我们建议使用两种最先进的技术，定量 通过单细胞分析进行灌注 PET 成像和细胞免疫表型分析 [单细胞 RNA-seq、细胞 外周血单核细胞转录组和表位索引（CITE）-seq]，结合 超声心动图。在具体目标 1 中，我们将评估 tildrakizumab 治疗是否会 (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）这种功能是否改善 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 细胞免疫表型与冠脉血管舒缩功能障碍及心肌的关系 机械学，基线时和 tildrakizumab 治疗 6 个月后。本提案的总体目标 是使用生理成像技术作为常规临床护理的一部分，以及新颖的细胞 免疫表型分析研究银屑病疾病和炎症与冠状血管的联系机制 健康和心脏的结构和功能。这项研究将解决未满足和需要的临床转化问题 牛皮癣疾病。这项研究将在全面职业发展的背景下完成 旨在为候选人（早期职业调查员）提供 CV 医学和 CV 培训的计划 成像，具备成为心血管医学领域独立医师科学家所需的技能。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，并最终为未来提供信息 治疗试验。杰出的指导团队和由该领域知名科学家组成的咨询委员会 CV医学、CV成像、风湿病学、皮肤病学、免疫学和细胞生物学的研究将指导 候选人在获奖期间向科学独立过渡。