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领域的独立研究者和医生科学家，以推动移植和组织工程器官领域的发展。他在麻省理工学院接受Robert Langer教授的本科培训，在宾夕法尼亚大学进行细胞粘附研究，并在马萨诸塞州总医院和加州大学洛杉矶分校医学中心接受外科培训，从而证明了他对这一目标的持续承诺。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提供了坚实的基础。现在在西北大学，他的角色是开发肝脏组织工程的研究计划，他得到了他的部门和导师的坚定支持。 Wertheim博士的近期目标是利用K 08奖的受保护的研究时间和导师结构来提高他在肝脏病理生物学方面的知识和科研技能，以有效地研究肝细胞功能和对3D基质环境的反应，最终目标是开发用于治疗性移植的组织工程器官。尽管开发了蛋白酶抑制剂来治疗丙型肝炎，但在可预见的未来，由于美国肥胖症的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，肝病将继续成为主要的公共卫生问题。肥胖和相关疾病发病率的增加不仅会增加对可移植生物人工 肝脏，还有其他器官。 Wertheim博士的实验室已经开发出了由脱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，这些生物反应器是灌注培养系统，肝细胞在来自脱细胞啮齿动物组织的全器官3D肝脏基质中生长。 本提案的目的是在表明SAMS中的细胞外基质增强使用诱导多能干细胞技术（iPS-肝细胞）开发的肝细胞活性的初步数据基础上取得进展。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，和2）将SAMS与比全长基质分子更有效的新型信号肽联合收割机组合，以进一步增强iPS-肝细胞功能。 Wertheim博士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经验丰富的内科医生兼科学家。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肝毒素介导的肝癌发生方面具有特殊的专业知识。Richard绿色博士是西北大学肝病科主任。他的研究专长是肝胆盐代谢的分子发病机制。Samuel Stupp博士是世界知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博士是纳米技术的世界领导者，他的研究继续推进生物功能肽领域。Michael Abechte博士是西北大学移植部主任，综合移植中心的创始主任，是2011年NIH资助的排名第七的外科医生。 该提案利用西北大学的培训计划，中心和研究所的优势，以加强Wertheim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。综合移植中心将成为Wertheim博士的重心，在肝脏病学，肝脏病理学和各级科学研究导师的研讨会。Wertheim博士是IBNAM的成员，IBNAM是一个多学科的合作机构，拥有最先进的设施，包括用于开发生物功能肽和3D生物打印的肽测序。Wertheim博士也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的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。 该建议以及组装的环境和指导结构解决了双重但互补的目的：1）通过结构化的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，以及2）使用星状细胞和尖端生物功能肽来评估组织工程肝脏支架中的关键细胞-基质和细胞-细胞关系。这些目标，以及大学的坚定支持，将为Wertheim博士提供必要的技能，以实现他成为肝组织工程独立的外科医生科学家的目标。