Optimization and control of hepatocyte activity via biofunctional modification

简介(申请人提供)：Wertheim博士的职业目标是成为肝脏组织工程领域的独立研究员和内科科学家，以推动移植和组织工程器官领域的发展。他在麻省理工学院与大学细胞黏附研究生罗伯特·兰格教授一起接受本科培训，证明了他对这一目标的持续承诺。并在马萨诸塞州总医院和加州大学洛杉矶分校医疗中心接受外科培训。韦特海姆博士作为一名移植外科医生所受的训练，以及生物医学工程方面的科学背景，为他提出的肝脏组织工程研究提供了坚实的基础。现在在西北大学，他的角色是开发一个肝脏组织工程的研究项目，他得到了系里和导师们的坚定支持。Wertheim博士的近期目标是利用K08奖的保护性研究时间和导师结构，增强他在肝脏病理生物学方面的知识和科研技能，有效地研究肝细胞功能和对3D基质环境的响应，最终目标是开发用于治疗性移植的组织工程器官。尽管开发了用于治疗丙型肝炎的蛋白酶抑制剂，但在可预见的未来，由于肥胖在美国流行导致代谢综合征、非酒精性脂肪性肝炎(NASH)、高血压和糖尿病，肝病仍将是一个主要的公共卫生问题。肥胖症和相关疾病发病率的增加，不仅会增加对可移植生物人工材料的需求 肝脏，但其他器官也是。韦特海姆博士的实验室已经开发出小型生物人工微型支架(SAMS)，这种支架是由无细胞的大鼠肝脏支架制成的。这种环境允许以受控的方式研究肝细胞与细胞外基质分子、生长因子和其他细胞的相互作用。他的实验室还开发了创新的流动生物反应器，这是一种灌流培养系统，肝细胞在从脱细胞啮齿动物组织中提取的全器官3D肝基质中生长。这项建议的目的是在初步数据的基础上取得进展，这些数据表明SAMS中的细胞外基质增强了利用诱导多能干细胞技术(iPS-肝细胞)培养的肝细胞的活性。本研究的目的是：1)评价调节细胞外基质重塑的星状细胞对自发性多发性硬化肝细胞功能的影响；2)将自发性多发性硬化与比全长基质分子更有效的新型信号肽结合起来，进一步增强自发性多发性硬化肝细胞的功能。西北大学的科学环境、导师团队和职业发展计划都是围绕韦特海姆博士的目标创建的，他的目标是利用受保护的时间来丰富他对肝细胞病理生理学和纳米技术的知识和理解，以帮助缩小外科培训造成的差距。贾纳拉丹·雷迪博士是韦特海姆博士的主要导师，也是西北大学病理学系经验丰富的内科科学家。雷迪博士的实验室在肝细胞前体细胞生物学、细胞分离、肝脏特异性异常动物模型的开发以及肝毒素介导的肝癌发生方面拥有特殊的专业知识。理查德·格林博士是西北大学肝病科主任。他的研究方向是肝脏胆盐代谢的分子发病机制。塞缪尔·斯图普博士是世界著名的纳米技术研究人员。他是西北大学生物纳米医学研究所(IBNAM)的所长，韦特海姆博士是该研究所的成员。斯图普博士是纳米技术领域的世界领先者，他的研究继续推动生物功能多肽领域的发展。迈克尔·阿贝卡西斯博士是西北大学移植科主任，也是综合移植中心的创始主任，是2011年美国国立卫生研究院资助的排名第七的外科医生。这项建议利用西北大学的培训计划、中心和研究所的力量，促进韦特海姆博士的职业发展，并将肝细胞生物学知识应用于他的肝脏组织工程研究。综合移植中心将是Wertheim博士的重心，举办肝病学、肝脏病理学研讨会，并在所有级别的科学研究中提供指导。韦特海姆博士是IBNAM的成员，IBNAM是一个合作的多学科研究所，拥有最先进的设施，包括用于开发生物功能多肽和3D生物打印的多肽测序。韦特海姆博士也是西北大学生命过程化学研究所的成员。中电促进物理和生命科学家之间的跨学科合作，以解决“大问题”的复杂性。CLP设施专门从事小分子化合物的高通量机器人分析，以及从分子到整个动物的复杂成像资源。这项建议以及组装的环境和指导结构实现了双重但互补的目的：1)通过结构化的指导和受保护的科学框架，提高Wertheim博士在肝脏病理生物学生理学方面的科学技能；2)使用星状细胞和尖端生物功能肽来评估关键的细胞-基质和细胞-细胞关系，这是组织工程肝脏支架中的关键技术。这些目标和大学的坚定不移的支持，将为韦特海姆博士提供必要的技能，以实现他成为一名独立的肝脏组织工程外科医生兼科学家的目标。

DESCRIPTION (provided by applicant): Dr. Wertheim's career goal is to become an independent investigator and physician-scientist in liver tissue engineering to advance the fields of transplantation and tissue engineered organs. He has demonstrated a continued commitment to this objective through his undergraduate training at MIT with Prof. Robert Langer, graduate research in cell adhesion at the Univ. of Pennsylvania and surgical training at the Massachusetts General Hospital and UCLA Medical Center. Together, Dr. Wertheim's training as a transplant surgeon and scientific background in biomedical engineering provide a strong foundation for his proposed research in liver tissue engineering. Now at Northwestern University, his role is to develop a research program in liver tissue engineering, and he has unwavering support from his Department and mentors. Dr. Wertheim's immediate goal is to use the protected research time and mentorship structure of the K08 Award to enhance his knowledge and scientific research skills in liver pathobiology to effectively study hepatocellular function and response to 3D matrix environments with the eventual goal of developing a tissues engineered organ for therapeutic transplantation. Despite the development of protease inhibitors to treat Hepatitis C, liver disease will continue to be a major public health problem in the foreseeable future due to the obesity epidemic in the US leading to metabolic syndrome, nonalcoholic steatohepatitis (NASH), hypertension and diabetes. The increased incidence of obesity, and associated diseases, will not just increases the need for transplantable bioartificial livers, but other organs as well. Dr. Wertheim's lab has developed Small bioArtificial, Micro-sized Scaffolds (SAMS) that are made from an acellular rat liver scaffold. This environment allows the interaction of hepatocytes with extracellular matrix molecules, growth factors, and other cells to be studied in a controlled manner. His lab has also developed innovative flow bioreactors that are perfusion culture systems where hepatocytes grow within whole-organ 3D liver matrices derived from decellularized rodent tissue. The goals of this proposal are to advance upon preliminary data indicating that the extracellular matrix in SAMS enhances the activity of hepatocytes developed using induced pluripotent stem cell technology (iPS- hepatocytes). The Aims are 1) To evaluate the influence of stellate cells, which regulate extracellular matrix remodeling, on the functioning of iPS-hepatocytes in SAMS and 2) To combine SAMS with novel signaling peptides that are more efficient than full-length matrix molecules, to further enhance iPS-hepatocyte function. The scientific environment at Northwestern, the mentorship team and career development plan have been created around Dr. Wertheim's objective to use protected time to enrich his knowledge and understanding of hepatocyte pathophysiology and nanotechnology to help "close the gap" created by surgical training. Dr. Janaradan Reddy is Dr. Wertheim's primary mentor and an experienced physician-scientist in the Department of Pathology at Northwestern. Dr. Reddy's laboratory has particular expertise in hepatocyte progenitor cell biology, cell isolation, development of animal models with liver-specific abnormalities and a particular focus on hepatotoxin-mediated hepatocarcinogenesis. Dr. Richard Green is the Chief of the Section of Hepatology at Northwestern. His research specializes in the molecular pathogenesis of hepatic bile salt metabolism. Dr. Samuel Stupp is a world-renowned researcher in nanotechnology. He is the Director of the Institute for BioNanotechnology in Medicine (IBNAM) at Northwestern, of which Dr. Wertheim is a member. Dr. Stupp is a world leader in nanotechnology and his research continues to advance the field of biofunctional peptides. Dr. Michael Abecassis is the Chief of the Division of Transplantation at Northwestern, the Founding Director of the Comprehensive Transplant Center, and was the 7th highest ranked surgeon funded by the NIH in 2011. This proposal leverages the strength of Northwestern's training programs, Centers and Institutes to enhance Dr. Wertheim's career development and apply knowledge of hepatocyte biology to his liver tissue engineering research. The Comprehensive Transplant Center will be Dr. Wertheim's center of gravity with seminars in hepatology, liver pathology and mentors in scientific research at all levels. Dr. Wertheim is a member of IBNAM that is a collaborative, multidisciplinary institute with state-of-the art facilities including peptide sequencing for development of biofunctional peptides and 3D bioprinting. Dr. Wertheim is also a member of the Chemistry of Life Processes (CLP) Institute at Northwestern. CLP fosters transdisciplinary collaboration among physical and life scientists to address the complexity of "big questions." CLP facilities specialize in high throughput robotic analysis of small molecular compounds and sophisticated imaging resources that span length scales from molecules to whole animals. This proposal, and the assembled environmental and mentoring structure, addresses dual, but complementary purposes: 1) To advance Dr. Wertheim's scientific skills in the physiology of liver pathobiology through a structured mentorship and protected scientific framework and 2) To use stellate cells and cutting- edge biofunctional peptides to evaluate critical cell-matrix and cell-cell relationshis in a tissue engineered liver scaffold. These objectives, and the unwavering support of the University, will provide Dr. Wertheim with the skills necessary to attain his goal to become an independent, surgeon-scientist in liver tissue engineering.