Blood-based biomarker amplification using high intensity focused ultrasound (HIFU

使用高强度聚焦超声 (HIFU) 进行基于血液的生物标志物扩增

• 批准号: 8514604
• 负责人: Tatiana Khokhlova
• 金额: $ 14.45万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8514604
• 关键词: Ablation; Acoustics; Acute; Affect; Animal Model; Animals; Area; Articular Range of Motion; Award; Benign; Benign Prostatic Hypertrophy; Biological Markers; Biopsy; Biotechnology; Blood; Blood Circulation; Blood flow; Blood specimen; Cancer Patient; Cardiac; Cells; Clinic; Collaborations; Cytolysis; Detection; Development; Devices; Diagnosis; Dimensions; Disease; Doctor of Philosophy; Elderly man; Engineering; Environment; Explosion; Extracellular Space; Failure; Focused Ultrasound Therapy; Fred Hutchinson Cancer Research Center; Frequencies; Furuncles; Gel; Goals; Heat-Shock Response; Heating; Heterogeneity; Histocompatibility Testing; Hour; Human; Individual; Infection; Internal Medicine; K-Series Research Career Programs; Laboratories; Lead; Length; Liver; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Measurement; Mechanics; Medical; Medical Technology; Medicine; Mentors; Methods; Metric; MicroRNAs; Microbiology; Monitor; Morbidity - disease rate; Motion; Nature; Outcome; Output; Pancreas; Patients; Pediatric Hospitals; Physics; Physiologic pulse; Plasma; Procedures; Prostate; Prostate-Specific Antigen; Protocols documentation; Public Health; Relative (related person); Reporting; Research; Research Personnel; Risk; Sampling; Scheme; Scientist; Serum; Shock; Source; Techniques; Technology; Temperature; Testing; Time; Tissue Sample; Tissues; Translating; Tumor Tissue; Ultrasonic Therapy; Ultrasonography; Ultrasound, High-Intensity Focused, Transrectal; Universities; Washington; Water; Work; absorption; base; cancer classification; cancer diagnosis; clinical application; clinically relevant; cost; design; heat injury; improved; in vivo; in vivo Model; interest; medical schools; millisecond; novel; novel therapeutics; rectal; respiratory; screening; therapy design; tool; tumor

DESCRIPTION (provided by applicant): Benign prostate hyperplasia (BPH) and prostate cancer are very common prostate conditions in elderly men, and current non-invasive screening tools, e.g., Prostate Specific Antigen (PSA) tests, often fail to differentiate between the two. Ths failure leads to extensive use of prostate biopsies to obtain tissue samples for histological examination. Not only is this procedure uncomfortable, unpleasant and prone to complications, the rate of false negatives is high due to the multifocal nature of prostate cancer. Development of reliable blood-based biomarkers for prostate cancer would eliminate the need for invasive biopsies, but still remains an unmet challenge. Recently a class of small regulatory RNAs - micro-RNAs - has shown great promise as a blood-based biomarker for prostate cancer diagnosis and prognostication. However, according to the studies reported to date, the sensitivity of this technique is too low to be clinically relevant. High intensity focused ultrasoud (HIFU) therapy is a non-invasive ablation method, in which ultrasound energy from an extracorporeal or trans-rectal source can be focused within the body to induce thermal denaturation of tissue at the focus without affecting surrounding tissues. A novel type of HIFU exposure designed for inducing purely mechanical erosion of tissue, viz., histotripsy, was recently proposed. This type of exposure utilizes highly nonlinear short HIFU pulses to induce localized boiling at the focus in as fast as a few milliseconds. Erosive damage to tissue is produced by the explosion of the resulting boiling bubble and its interaction with the HIFU field. The ultimate goal of this proposal is to use HIFU for localized targeted lysis of selected areas of the prostate that will lead to the release of cell contents into the extracellular space and increae the concentration of tissue-specific micro-RNAs in the circulation. Thus, the sensitivity of micro-RNA-based tests for diagnosis of prostate conditions will be significantly enhanced. This combined technique may thus be termed "non-invasive biopsy". The Specific Aims of this proposal are: 1) characterize high amplitude, nonlinear acoustic outputs of the HIFU sources relevant to trans-rectal applications, 2) observe the erosive effect produced by HIFU in transparent tissue-mimicking gel phantoms and 3) ex-vivo tissue with different pulsing protocols, 4) optimize and apply HIFU exposures causing localized tissue lysis in a small animal tumor model in-vivo and 5) determine if the concentration of tumor-specific micro-RNAs in the circulation is enhanced following HIFU- induced localized tumor lysis in a small animal model. The long-term research goal of the candidate applying for this Career Development Award (Tatiana Khokhlova, PhD) is to optimize this non-invasive biopsy technique, transform the corresponding HIFU device to work trans-rectally, and translate the concept into a clinically useful approach to perform non-invasive biopsy of the prostate. The research environment at the University of Washington that includes experts in medical ultrasound (Applied Physics Laboratory, Center for Industrial and Medical Ultrasound), microbiology (Fred Hutchinson Cancer Research Center) and medicine (School of Medicine) is perfect for achieving this goal. Dr. Khokhlova is an ultrasound physicist and engineer, and has worked extensively in the field of medical applications of ultrasound technology. This interdisciplinary background enables Dr. Khokhlova to successfully collaborate with both clinicians and scientists. Dr. Khokhlova plans to pursue research in novel therapeutic ultrasound technologies, to continue current collaborations with the Fred Hutchinson Cancer Research Center and Children's Hospital, and thus be connected with both scientists and clinicians and facilitate more rapid transfer of the exciting new developments in medical ultrasound directly into the clinic. The primary reason for applying for this Award is to permit Dr. Khokhlova to gain further expertise in biotechnology and internal medicine and to develop into an independent investigator while being mentored by three highly successful researchers, Drs. Joo Ha Hwang, Lawrence Crum, and Muneesh Tewari.

描述（由申请人提供）：良性前列腺增生（BPH）和前列腺癌是老年男性中非常常见的前列腺疾病，目前的非侵入性筛查工具，例如，前列腺特异性抗原（PSA）测试，往往无法区分两者。这种失败导致广泛使用前列腺活检来获得组织样本进行组织学检查。这种手术不仅不舒服、不愉快并且容易出现并发症，而且由于前列腺癌的多灶性，假阴性率很高。开发可靠的基于血液的前列腺癌生物标志物将消除对侵入性活检的需要，但仍然是一个未满足的挑战。最近，一类小的调节RNA-micro-RNA-显示出作为用于前列腺癌诊断和鉴别的基于血液的生物标志物的巨大前景。然而，根据迄今为止报告的研究，该技术的灵敏度太低，不具有临床相关性。高强度聚焦超声（HIFU）治疗是一种非侵入性消融方法，其中来自体外或经直肠源的超声能量可以聚焦在体内，以诱导焦点处组织的热变性，而不影响周围组织。一种设计用于诱导组织的纯机械侵蚀的新型HIFU暴露，即，组织解剖学最近被提出。这种类型的曝光利用高度非线性的短HIFU脉冲，以在几毫秒内在焦点处诱导局部沸腾。对组织的损伤是由产生的沸腾气泡的爆炸及其与HIFU场的相互作用产生的。该建议的最终目标是使用HIFU对选定区域的局部靶向裂解。 前列腺将导致细胞内容物释放到细胞外空间，并增加循环中组织特异性micro-RNA的浓度。因此，用于诊断前列腺病症的基于微小RNA的测试的灵敏度将显著增强。因此，这种组合技术可以被称为“非侵入性活检”。该提案的具体目标是：1）表征与经直肠应用相关的HIFU源的高振幅、非线性声输出，2）观察由HIFU在透明的仿组织凝胶体模中产生的侵蚀效果，以及3）用不同的脉冲协议离体组织，4）优化和应用HIFU暴露，在体内小动物肿瘤模型中引起局部组织裂解，和5）确定肿瘤特异性微-在小动物模型中，HIFU诱导的局部肿瘤溶解后循环中的RNA增强。申请该职业发展奖的候选人（Tatiana Khokhlova博士）的长期研究目标是优化这种无创活检技术，将相应的HIFU设备改造为经直肠工作，并将该概念转化为临床有用的方法来进行前列腺的无创活检。华盛顿大学的研究环境包括医学超声（应用物理实验室，工业和医学超声中心），微生物学（弗雷德哈钦森癌症研究中心）和医学（医学院）的专家，非常适合实现这一目标。Khokhlova博士是一位超声物理学家和工程师，在超声技术的医学应用领域有着广泛的工作经验。这种跨学科的背景使Khokhlova博士能够成功地与临床医生和科学家合作。Khokhlova博士计划继续研究新的治疗性超声技术，继续与Fred哈钦森癌症研究中心和儿童医院的合作，从而与科学家和临床医生建立联系，并促进更快地将医学超声领域令人兴奋的新发展直接转移到临床。申请该奖项的主要原因是允许Khokhlova博士在生物技术和内科方面获得进一步的专业知识，并在三位非常成功的研究人员Joo Ha Hwang博士，Lawrence Crum博士和Muneesh Tewari的指导下发展成为独立的研究人员。