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

• 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
• 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

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中的独立研究者和医师 - 科学家，以推动移植和组织工程器官的领域。他通过在MIT的本科培训与罗伯特·兰格（Robert Langer）教授，大学的细胞粘附研究生研究表现出对这一目标的持续承诺。马萨诸塞州总医院和加州大学洛杉矶分校医疗中心的宾夕法尼亚州和外科培训。 Wertheim博士作为移植外科医生和生物医学工程的科学背景的培训为他在肝组织工程领域提议的研究奠定了坚实的基础。现在在西北大学，他的角色是在肝组织工程中制定研究计划，他的部门和导师的支持坚定不移。 Wertheim博士的近期目标是利用K08奖的受保护的研究时间和指导结构来增强他在肝病原体学方面的知识和科学研究技能，以有效研究肝细胞功能，并以对3D矩阵环境的反应，最终通过开发针对治疗器官进行治疗器官进行疗法移植。尽管蛋白酶抑制剂治疗丙型肝炎，但由于美国的肥胖症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，肝病将继续成为一个主要的公共卫生问题。肥胖症和相关疾病的发生率的增加不仅会增加对可移植的生物人工的需求 肝，但其他器官也是如此。 Wertheim博士的实验室开发了由小鼠肝支架制成的小型生物人工，微型支架（SAM）。该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量生物反应器，这些生物反应器是灌注培养基系统，在该系统中，肝细胞在全器3D肝脏基质中生长，这些肝脏源自脱细胞啮齿动物组织。 该提案的目标是促进初步数据，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）开发的肝细胞活性。目的是1）评估恒星细胞的影响，这些细胞调节细胞外基质重塑，对SAMS中IPS-羊皮细胞的功能和2）的功能，将SAM与新型信号肽相结合，这些肽比全长的基质分子更有效，以进一步增强IPS-HepaTocyte ips-hepatocyte function。 西北地区的科学环境，指导团队和职业发展计划是围绕韦特海姆博士的目标创建的，该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了解和理解，以帮助手术培训创建的“差距”。 Janaradan Reddy博士是Wertheim博士的主要导师，也是西北病理学系的经验丰富的医师科学家。 Reddy博士的实验室在肝细胞祖细胞生物学，细胞分离，具有肝脏特异性异常的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具有特殊的专业知识。理查德·格林（Richard Green）博士是西北部肝病学部分的负责人。他的研究专门研究肝胆汁盐代谢的分子发病机理。塞缪尔·斯图普（Samuel Stupp）博士是纳米技术的世界知名研究员。他是西北地区的医学生物技术研究所（IBN）的主任，韦特海姆（Wertheim）博士是成员。 Stupp博士是纳米技术的世界领导者，他的研究继续推进生物功能肽的领域。 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.全面的移植中心将是Wertheim博士的重心中心，在各级科学研究中，肝病学，肝病学和导师的研讨会。 Wertheim博士是IBNAN的成员，是一家合作，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和3D生物印刷的肽测序。 Wertheim博士也是西北部生活过程化学过程（CLP）研究所的成员。 CLP促进了身体和生活科学家之间的跨学科合作，以解决“大问题”的复杂性。 CLP设施专门研究小分子化合物和复杂成像资源的高吞吐物机器人分析，这些成像资源跨越了长度从分子到整个动物。 这项建议以及组装的环境和指导结构解决了双重的，但互补的目的：1）通过结构化的指导和受保护的科学框架和2）提高Wertheim博士在肝病原体学生理学方面的科学技能，并使用Stellate Cellate细胞和效力边缘生物触发的肽来评估临界细胞和临界细胞之间的研究。这些目标以及大学的坚定支持，将为Wertheim博士提供所需的技能，以达到他成为肝组织工程中独立的外科医生科学家的目标。