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

项目总结/摘要 SharmilaDorbala博士是哈佛医学院放射学副教授，也是一名医生/科学家 布里格姆妇女医院（Brigham and Women's Hospital，BWH）她的职业生涯致力于以患者为导向的研究，重点是 心脏淀粉样变性她通过一系列的研究对心脏淀粉样变性领域做出了独立的贡献。 利用分子成像对心脏淀粉样变性进行表型的实质性研究， 管理这个条件。她的研究计划是有影响力的，无论是直接和通过有效的指导， 下一代淀粉样变性研究者Dorbala博士成功指导了26名博士前和博士后 以病人为导向的研究项目的受训人员。她目前是两个活跃的NIH R 01赠款的PI， 来自AHA和基金会/工业来源的资金。她的计划提供了一个独特的机会，POR由于 到哈佛公共卫生学院临床研究项目资源的交叉点 和BWH心血管成像T32程序。她的学员在全国范围内展示了他们的工作， 在国际上发表论文，并获得研究奖和试点赠款。 该奖项中提出的新研究目标为辅助干预奠定了基础， 甲状腺素运载蛋白心脏淀粉样变性（ATTR-CA）治疗和新的基于图像的个性化策略，以预测 治疗失败。她将评估（1）声孔效应，一种治疗性超声技术， 灌注，并因此改善抗原纤维药物的递送;（2）免疫抑制剂的鸟枪法宏基因组测序。 肠道微生物组，为开发基于营养的辅助疗法提供信息;（3）99 mTc-放射组学 焦磷酸盐SPECT/CT，以评估治疗反应，和（4）基于机器学习的CT衍生的肌肉减少症 预测存活率的指标。这项研究具有重要的临床意义。目前批准的TTR 稳定/沉默药物，虽然挽救了大多数人的生命，但对大约30%的患者无效。此外，委员会认为， 虽然这些疗法改善了临床结果，但它们不能治疗淀粉样蛋白原纤维。纤维靶向治疗具有 迄今为止还不成功，可能是由于原纤维的存在导致的不良间质药物递送。的 该K24项目的拟议指导和研究活动的结果可能不仅大大 改善这些重症患者的预后并减轻HF症状，但也改变了她的患者- 一个以研究为导向的计划，变成一个正式的个性化的指导计划，重点是预防心脏病 淀粉样变性导致的衰竭

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.