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

项目摘要/摘要 莎米拉·多巴拉博士是哈佛医学院放射学副教授、内科医生/科学家 在布里格姆妇女医院(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。她为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表型的实质性研究以诊断和 管理好这一状况。她的研究计划是有影响的，无论是直接的，还是通过对 下一代淀粉样变性病研究人员。多巴拉博士已经成功地指导了26名博士后和博士后 以病人为中心的研究项目的实习生。她目前是两项有效的NIH R01拨款的PI，还拥有 资金来自AHA和基金会/工业来源。她的计划为POR提供了一个独特的机会 哈佛大学公共卫生学院临床研究项目的资源交集 和BWH心血管成像T32计划。她的导师已经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拨款。 该奖项中提出的新研究目标为辅助干预奠定了基础，以增强 经甲状腺激素心脏淀粉样变性(ATTR-CA)的治疗和新的基于图像的个性化预测策略 治疗失败。她将评估(1)超声手术，这是一种治疗心肌梗死的超声技术 灌流，从而改善抗纤维药物的输送；(2)鸟枪式元基因组测序 肠道微生物组为营养辅助疗法的发展提供信息；(3)99mTc-放射性组学 焦磷酸盐SPECT/CT用于评估治疗反应，以及(4)基于机器学习的CT来源的骨质疏松症 预测存活率的指标。本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， 虽然这些疗法改善了临床结果，但它们并不治疗淀粉样原纤维。纤维靶向治疗有 到目前为止还没有成功，可能是因为纤维的存在导致间质药物输送不佳。这个 这个K24项目拟议的指导和研究活动的结果可能不仅是实质性的 改善这些重病患者的预后并缓解心力衰竭症状，但也改变了她的患者- 将研究计划转化为正式的个性化指导计划，重点是预防心脏 淀粉样变性失败。

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.