Liver Cancer: pre-Malignant Stiffening, Membrane Transduction, & Nuclear Rheology

 描述(申请人提供)：PSoC Penn肝癌：癌前硬化、膜转导和核流变学，癌症物理学的跨学科性质需要跨越多个边界的高效和有效的相互作用。我们选择关注原发性肝癌，主要是肝细胞癌(HCC)，这是一种高度致病的肿瘤，是全球癌症死亡的第三大常见原因。肝细胞癌几乎总是发生在终末期肝纤维化的背景下，称为肝硬变，新的原位测量肝脏硬度的方法正在出现，成为预测肝细胞癌相对风险的有效指标。肝脏僵硬的患者表现出明显的肝癌发病率增加，但临床接受度无疑将有助于--甚至需要--这里提出的研究。我们试图确定人类肝癌与新鲜原代标本之间的关系的性质，肝组织的力学机制，对细胞的信号，以及核力学在DNA稳定性和肿瘤生长中的作用。宾夕法尼亚大学的五名临床医生定期为患有肝病和肝癌的患者或样本看病，他们参与了拟议的PSOC宾夕法尼亚大学，因此影响该诊所的机会是有形的。在制定这一贯穿各领域的建议时，有3 为了更好地代表研究项目和2个核心，我们提出了一个多PI领导计划，以最好地代表不同的专业知识和责任领域：Dennis Discher博士(工程应用科学教授，研究生团体物理学，细胞与分子生物学)联系PI，行政核心主管，项目3核流变学：癌细胞系专业知识的PI。Paul Janmey博士(生理学、物理学和生物工程学教授)，项目1肝脏力学：癌细胞系专业知识。丽贝卡·威尔斯医学博士(Assoc.医学、病理学和实验室医学教授)Core-1肝癌组织和模型的PI：肝病机制方面的专业知识。大卫·E·卡普兰医学博士(医学助理教授兼肝病科主任)共同主持了Core-1肝癌组织和模型：肝癌的临床专业知识。博士(物理和化学教授)派，核心-2理论：统计物理建模的专业知识。宾夕法尼亚大学是一个单一的综合校园，中心内的所有实验室都可以在5-10分钟内步行到达，宾夕法尼亚大学医疗中心医院为费城地区提供服务，拥有全国最大的肝病中心之一。为了将拟议的PSOC宾夕法尼亚大学整合到大学在癌症方面广泛而深入的努力中，PSOC的所有领导人和教职员工都将成为宾夕法尼亚大学艾布拉姆森癌症中心的成员(如果他们还没有加入)。艾布拉姆森癌症中心主任迟文当教授将担任Pilot Project-1的PI，并将成为中心咨询委员会的关键成员。更广泛地说，PSOC宾夕法尼亚大学将通过教育和外联支持各种计划，旨在建立一个充满活力的学生和研究员社区，他们体现了理解癌症物理学的多学科方法，目的是改变下一代科学家、工程师和临床医生。

 DESCRIPTION (provided by applicant): PSOC Penn Liver Cancer: pre-Malignant Stiffening, Membrane Transduction, & Nuclear Rheology, The Transdisciplinary nature of Cancer Physics requires efficient and effective interactions across multiple boundaries. We have chosen to focus on primary liver cancer, predominantly hepatocellular carcinoma (HCC), which are highly morbid tumors that represent the third most common cause of cancer death worldwide. HCC almost always arises in the setting of end-stage liver fibrosis, termed cirrhosis, and new in situ methods of measuring liver stiffness are emerging as effective predictors of the relative risk of HCC. Patients with stiffer livers demonstrate dramatically increased rates of HCC, but clinical acceptance will no doubt be helped by - or even require - studies proposed here. We seek to determine the nature of the relationships between human HCC with fresh primary samples and the mechanics of liver tissues, the signals to cells, and the roles of nuclear mechanics in DNA stability and tumor growth. Five clinicians at Penn who regularly see patients or samples with liver disease and liver cancer are involved in the proposed PSOC Penn, and so the opportunities to impact the Clinic are tangible. In formulating this cross-cutting proposal with 3 Research Projects and 2 Cores, we propose a Multi-PI Leadership Plan to best represent the diverse areas of expertise and responsibility: Dennis Discher PhD (Prof. Eng'g Appl Sci, Grad Groups Physics, Cell & Molec Biol) Contact PI, Admin Core Lead, PI of Project-3 Nuclear Rheology: Cancer Cell line Expertise. Paul Janmey PhD (Prof. Physiology, Physics, and Bioengineering) PI of Project-1 Liver Mechanics: Cancer Cell line Expertise. Rebecca Wells MD (Assoc. Prof. Medicine, Pathology, and Laboratory Medicine) PI of Core-1 Liver Cancer Tissue and Models: Expertise in Mechanisms of Liver Disease. David E. Kaplan MD (Asst. Professor of Medicine, and Director of Hepatology) Co-PI of Core-1 Liver Cancer Tissue and Models: Clinical Expertise in Liver Cancer. Andrea Liu PhD (Prof. Physics and Chemistry) PI of Core-2 Theory: Expertise in Statistical Physics Modeling. Penn is a single, integrated Campus, with all of the labs involved in the Center walkable within 5-10 minutes, and Penn's Medical Center Hospital serves the greater Philadelphia area with one of the larger liver disease centers in the country. To integrate the proposed PSOC Penn within the University's broad and deep efforts in Cancer, all leaders and faculty members of the PSOC will become members of Penn's Abramson Cancer Center (if they are not already). The Director of the Abramson Cancer Center, Prof. Chi Van Dang, will be PI of Pilot Project-1 and will be a key member of the Center Advisory Committee. More broadly, the PSOC Penn will support through Education & Outreach a wide variety of programs that aim to build a vibrant community of students and fellows who embody the multidisciplinary approach to understanding the physics of cancer with an aim of transforming the next generation of scientists, engineers and clinicians.