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.

项目概要/摘要 Sharmila Dorbala 博士是哈佛医学院放射学副教授，也是一名医生/科学家 在布莱根妇女医院（BWH）。她致力于以患者为中心的研究，重点关注 心脏淀粉样变性。她通过一系列的研究独立地为心脏淀粉样变性领域做出了贡献 利用分子成像对心脏淀粉样变性进行表型分析以诊断和诊断的实质性研究 控制这种情况。她的研究项目具有影响力，无论是直接影响还是通过对研究人员的有效指导 下一代淀粉样变性研究人员。 Dorbala 博士已成功指导了 26 名博士前和博士后 以患者为导向的研究项目的实习生。她目前是两项活跃的 NIH R01 资助项目的 PI，并且还拥有 来自 AHA 和基金会/行业来源的资金。她的项目为 POR 提供了独特的机会 哈佛大学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 计划。她的学员在全国范围内展示了他们的作品 在国际上发表论文，并获得研究奖项和试点资助。 该奖项提出的新研究目标为辅助干预措施奠定了基础，以增强 转甲状腺素蛋白心脏淀粉样变性 (ATTR-CA) 疗法和基于图像的新型个性化预测策略 治疗失败。她将评估 (1) 声孔法，这是一种增加心肌的治疗性超声技术 灌注，从而改善抗纤维药物的输送； (2)鸟枪法宏基因组测序 肠道微生物组为基于营养的辅助疗法的开发提供信息； (3) 99mTc-的放射组学 焦磷酸 SPECT/CT 用于评估治疗反应，以及 (4) 基于机器学习的 CT 衍生的肌肉减少症 预测生存的指标。这项研究具有重要的临床意义。目前已获批准的TTR 稳定/沉默药物虽然可以挽救大多数人的生命，但对大约 30% 的患者无效。而且， 虽然这些疗法改善了临床结果，但它们不能治疗淀粉样原纤维。原纤维靶向治疗已 迄今为止尚未成功，可能是由于原纤维的存在导致间质药物输送不良。这 该 K24 项目拟议的指导和研究活动的结果可能不仅会显着 改善结果并减轻这些重症患者的心力衰竭症状，同时也改变了她的患者- 将研究计划转变为正式的个性化指导计划，重点是预防心脏病 淀粉样变性失败。