Optimization and control of hepatocyte activity via biofunctional modification

通过生物功能修饰优化和控制肝细胞活性

基本信息

批准号：
9246530
负责人：
JASON A WERTHEIM
金额：
$ 16.17万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9246530
关键词：
Address Affect Alpha Cell Amino Acid Sequence Animals Area Artificial Liver Award Basic Science Bile fluid Biology Biomedical Engineering Bioreactors Cell Adhesion Cell Adhesion Molecules Cell Differentiation process Cell Maturation Cell Separation Cell physiology Cells Cellular biology Chemistry Cholesterol Chronic Coculture Techniques Complement Complex Data Development Development Plans Diabetes Mellitus Disease Drug Metabolic Detoxication Effector Cell Environment Epidemic Extracellular Matrix Force of Gravity Fostering Foundations Functional disorder Funding Future General Hospitals Genes Goals Growth Factor Hepatic Hepatic Stellate Cell Hepatitis Hepatitis C Hepatocarcinogenesis Hepatocyte Hepatology Human Hypertension Image Incidence Institutes Integrin Binding Investigation Knowledge Laboratories Length Life Liver Liver Failure Liver diseases Massachusetts Mediating Medical center Medicine Mentors Mentorship Metabolic syndrome Metabolism Methodology Modeling Modification Molecular Nanotechnology Natural regeneration Obesity Obesity associated disease Operative Surgical Procedures Organ Organ Donor Organ Transplantation Organ failure Pathogenesis Pathology Patients Pennsylvania Peptide Signal Sequences Peptides Performance Perfusion Pharmaceutical Preparations Phase Phenotype Physicians Physiology Procedures Process Protease Inhibitor Public Health Rattus Recruitment Activity Regenerative Medicine Research Research Methodology Research Personnel Research Proposals Resources Robotics Rodent Rodent Model Role Savings Science Scientist Signal Pathway Stem cells Structure Surgeon System Technology Therapeutic Therapeutic Uses Time Tissue Engineering Tissues Training Training Programs Transplant Surgeon Transplantation United States National Institutes of Health Universities Work angiogenesis animal model development bile salts bioprinting career career development dosage experience hepatotoxin induced pluripotent stem cell innovation interdisciplinary collaboration liver transplantation member multidisciplinary nanobiotechnology nonalcoholic steatohepatitis novel peptidomimetics prevent programs public health relevance response scaffold skills standard of care stellate cell stem success synthetic peptide three dimensional cell culture transplantation medicine undergraduate student

项目摘要

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.

描述（由申请人提供）：Wertheim 博士的职业目标是成为肝组织工程领域的独立研究者和医师科学家，以推进移植和组织工程器官领域的发展。通过在麻省理工学院接受罗伯特·兰格教授的本科培训，以及在大学细胞粘附方面的研究生研究，他表现出了对这一目标的持续承诺。宾夕法尼亚州医学中心和马萨诸塞州总医院和加州大学洛杉矶分校医学中心的外科培训。 Wertheim 博士作为移植外科医生的培训和生物医学工程的科学背景为他提出的肝脏组织工程研究奠定了坚实的基础。现在，他在西北大学负责开发肝脏组织工程研究项目，并得到了系和导师的坚定支持。 Wertheim 博士的近期目标是利用 K08 奖的受保护研究时间和导师结构来增强他在肝脏病理学方面的知识和科学研究技能，以有效研究肝细胞功能和对 3D 基质环境的反应，最终目标是开发一种组织工程化用于治疗性移植的器官。尽管开发了治疗丙型肝炎的蛋白酶抑制剂，但在可预见的将来，由于美国肥胖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。肥胖及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，还有其他器官。 Wertheim 博士的实验室开发了由无细胞大鼠肝脏支架制成的小型生物人工微型支架 (SAMS)。这种环境允许以受控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，这是一种灌注培养系统，其中肝细胞在源自脱细胞啮齿动物组织的全器官 3D 肝脏基质中生长。该提案的目标是基于初步数据，表明 SAMS 中的细胞外基质增强了使用诱导多能干细胞技术（iPS 肝细胞）开发的肝细胞的活性。目的是 1) 评估调节细胞外基质重塑的星状细胞对 SAMS 中 iPS 肝细胞功能的影响；2) 将 SAMS 与比全长基质分子更有效的新型信号肽结合起来，以进一步增强iPS-肝细胞功能。西北大学的科学环境、导师团队和职业发展计划都是围绕沃特海姆博士的目标创建的，即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“缩小手术培训造成的差距”。 Janaradan Reddy 博士是 Wertheim 博士的主要导师，也是西北大学病理学系一位经验丰富的医师兼科学家。 Reddy 博士的实验室在肝细胞祖细胞生物学、细胞分离、肝脏特异性异常动物模型的开发以及特别关注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 (Richard Green) 博士是西北大学肝病科主任。他的研究专门研究肝胆汁盐代谢的分子发病机制。 Samuel Stupp 博士是世界著名的纳米技术研究员。他是西北大学医学生物纳米技术研究所 (IBNAM) 的主任，Wertheim 博士是该研究所的成员。 Stupp 博士是纳米技术领域的世界领先者，他的研究不断推动生物功能肽领域的发展。 Michael Abecassis 博士是西北大学移植科主任、综合移植中心的创始主任，也是 2011 年 NIH 资助的排名第七的外科医生。该提案充分利用了西北大学的培训项目、中心和研究所旨在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到他的肝脏组织工程研究中。综合移植中心将成为Wertheim博士的重心，举办肝病学、肝脏病理学研讨会和各级科学研究导师。 Wertheim 博士是 IBNAM 的成员，IBNAM 是一家协作性多学科研究所，拥有最先进的设施，包括用于开发生物功能肽的肽测序和 3D 生物打印。 Wertheim 博士还是西北大学生命过程化学 (CLP) 研究所的成员。 CLP 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和复杂的成像资源，涵盖从分子到整个动物的长度尺度。该提案以及组装的环境和指导结构解决了双重但互补的目的：1）通过结构化指导和受保护的科学框架来提高 Wertheim 博士在肝脏病理生物学生理学方面的科学技能，2）使用星状细胞和切割- 边缘生物功能肽，用于评估组织工程肝脏支架中关键的细胞-基质和细胞-细胞关系。这些目标以及大学坚定不移的支持将为沃特海姆博士提供必要的技能，以实现他成为肝组织工程领域独立的外科医生科学家的目标。