Mentoring Patient Oriented Research in Innovative Imaging and High-dimensional Data Approaches to Improve Outcomes in Cardiac Amyloidosis

指导创新成像和高维数据方法中以患者为导向的研究，以改善心脏淀粉样变性的治疗结果

• 批准号: 10191887
• 负责人: Sharmila Dorbala
• 金额: $ 12.16万
• 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: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10191887
• 关键词: Address; Adult; Affect; Ammonia; Amyloid Fibrils; Amyloidosis; Award; Bacteria; Blood flow; Cardiac; Cardiac Volume; Cessation of life; Clinical; Clinical Research; Clinical Trials; Complement; Data; Databases; Deposition; Development; Diagnosis; Diet; Diphosphates; Drug Delivery Systems; Drug Targeting; EFRAC; Elderly; Excision; Failure; Feces; Foundations; Funding; Goals; Grant; Heart; Heart failure; Hospitals; Image; Image Analysis; Individual; Industrialization; International; Intervention; Light; Machine Learning; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Medicine; Mentors; Methods; Mid-Career Clinical Scientist Award (K24); Myocardial; Myocardial perfusion; Myocardium; Outcome; PET/CT scan; Paper; Patients; Perfusion; Pharmaceutical Preparations; Phase; Phenotype; Physicians; Plant Roots; Postdoctoral Fellow; Prealbumin; Prediction of Response to Therapy; Preventive; Protein Precursors; Proteins; Public Health Schools; Publishing; Radiology Specialty; Research; Research Activity; Research Personnel; Research Project Grants; Research Proposals; Resources; Rest; Risk; Sampling; Scientist; Shotguns; Source; Spearman Rank Correlation Coefficient; Symptoms; Technical Expertise; Techniques; Testing; Texture; Therapeutic; Training; Treatment Failure; Ultrasonography; United States National Institutes of Health; Woman; Work; X-Ray Computed Tomography; automated segmentation; base; cardiovascular imaging; career; clinical investigation; cohort; cost; data registry; effective therapy; extracellular; fecal microbiota; follow-up; frontier; gut microbiome; hazard; heart imaging; imaging approach; improved; improved outcome; innovation; interstitial; medical schools; metagenomic sequencing; mid-career faculty; molecular imaging; mortality; multidimensional data; next generation; novel; novel marker; novel strategies; novel therapeutics; nutrition; patient oriented research; personalized strategies; pre-doctoral; preservation; prevent; programs; radiomics; response; sarcopenia; single photon emission computed tomography; sonoporation; survival prediction; targeted treatment; treatment response; treatment strategy; β-amyloid burden

Project Summary/Abstract Dr Sharmila Dorbala is an Associate Professor of Radiology at Harvard Medical School and a physician/scientist at Brigham and Women's Hospital (BWH). She has devoted her career to patient-oriented research focusing on cardiac amyloidosis. She contributed independently to the field of cardiac amyloidosis through a succession of substantive studies utilizing molecular imaging to phenotype cardiac amyloidosis in order to diagnose and manage this condition. Her research program is impactful, both directly and through effective mentoring of the next generation of amyloidosis investigators. Dr. Dorbala has successfully mentored 26 pre- and post-doctoral trainees in patient- oriented research projects. She is currently PI of two active NIH R01 grants and also has funding from AHA and foundation/industrial sources. Her program provides a unique opportunity for POR due to the intersection of resources from programs in clinical investigation at the Harvard School of Public Health and the BWH cardiovascular imaging T32 program. Her mentees have presented their work nationally and internationally, published papers, and won research awards and pilot grants. The new research aims proposed in this award lay the foundation for adjunct interventions to enhance transthyretin cardiac amyloidosis (ATTR-CA) therapies and novel image-based personalized strategies to predict treatment failure. She will assess (1) sonoporation, a therapeutic ultrasound technique to increase myocardial perfusion and, consequently, improve delivery of antifibril drugs; (2) shotgun metagenomic sequencing of the gut microbiome to inform development of nutrition-based adjunct therapies; (3) radiomics of 99mTc- pyrophosphate SPECT/CT to assess treatment response, and (4) machine learning based CT-derived sarcopenia metric to predict survival. This research has important clinical implications. Currently approved TTR stabilizing/silencing drugs, though lifesaving for most, are not effective in about 30% of patients. Moreover, while these therapies improve clinical outcomes, they do not treat amyloid fibril. Fibril-targeted therapies have been unsuccessful to date, probably because of poor interstitial drug delivery due to the presence of fibril. The results of the proposed mentoring and research activities of this K24 project are likely to not only substantially improve outcomes and alleviate HF symptoms in these gravely ill patients, but also transform her patient- oriented research program into a formal individualized program of mentoring with a focus on preventing heart failure from amyloidosis.

项目摘要/摘要 Sharmila Dorbala博士是哈佛医学院放射学副教授，也是医师/科学家 在Brigham and妇女医院（BWH）。她致力于以患者为导向的研究专注于 心脏淀粉样变性。她通过一连串的 利用分子成像进行表型心脏淀粉样变性的实质性研究，以诊断和 管理这个条件。她的研究计划是直接和通过有效指导的影响 下一代淀粉样变性研究者。 Dorbala博士成功地指导了26个前后的指导 以患者为导向的研究项目的学员。她目前是两个活跃的NIH R01赠款的PI，也有 来自AHA和基金会/工业来源的资金。她的计划为POR提供了独特的机会 到哈佛公共卫生学院的临床调查计划中资源的交集 和BWH心血管成像T32程序。她的受训者在全国范围内介绍了他们的工作， 在国际上发表论文，并获得了研究奖和飞行员赠款。 该奖项中提出的新研究目的是辅助干预措施的基础 经硫代蛋白心脏淀粉样变性（ATTR-CA）疗法和基于图像的新型个性化策略来预测 治疗失败。她将评估（1）Sonoporation，这是一种治疗性超声技术，以增加心肌 灌注，因此改善了抗纤维药物的递送； （2）shot弹枪的宏基因组测序 肠道微生物组，以告知基于营养的辅助疗法的开发； （3）99mtc-的放射素学 焦磷酸SPECT/CT评估治疗反应，以及（4）基于机器学习的CT衍生的肌肉减少症 指标预测生存。这项研究具有重要的临床意义。目前已批准的TTR 稳定/沉默药物虽然大多数人的寿命在大约30％的患者中无效。而且， 尽管这些疗法改善了临床结果，但它们不治疗淀粉样蛋白原纤维。靶向原靶疗法具有 到目前为止未能成功，可能是由于由于纤维的存在而导致的间质药物递送不良。这 该K24项目的拟议指导和研究活动的结果不仅可能会实质 改善这些严重患者的预后和减轻HF症状，但也改变了她的患者 - 将研究计划定为正式的个性化指导计划，专注于预防心脏 淀粉样变性失败。