Tissue engineered substitute based on a system of autologous cells

基于自体细胞系统的组织工程替代品

基本信息

批准号：
7319674
负责人：
ATHANASSIOS SAMBANIS
金额：
$ 29.41万
依托单位：
GEORGIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7319674
关键词：
Acute Address Adult Allogenic Anatomy Antigen Presentation Pathway Antigens Application procedure Autoimmune Process Autoimmunity Autologous Cell Line Cell Survival Cell Therapy Cell physiology Cells Collaborations Cues Data Depth Development Diabetic mouse Diffuse Down-Regulation Embryo Encapsulated Endocrine Engineering Enteroendocrine Cell Environment Evaluation Exhibits Family suidae Fibroblasts Florida Funding Gene Delivery Genetic Glucose Goals Hepatic Hepatocyte Human Immune Immune response Immunosuppression Implant In Vitro Injection of therapeutic agent Insulin Insulin Infusion Systems Insulin-Dependent Diabetes Mellitus Intestines Invasive Islets of Langerhans Islets of Langerhans Transplantation Knowledge L Cells Life Locales Localized Metabolic Metabolism Methodology Methods Mus Myoblasts Nature Numbers Outcome Pancreas Pathway interactions Patients Pattern Phenotype Physiological Quality of life Range Recombinants Regulation Research Research Personnel Resources Rest Rodent Secretory Component Secretory Vesicles Signal Transduction Source Staging Stem cells Stimulus System Technology Testing Therapeutic immunosuppression Tissue Donors Tissue Engineering Tissues Transcriptional Regulation Transgenes Transplant Recipients Treatment Efficacy USA Georgia Universities Western Asia Georgia Work base blood glucose regulation cell type cellular engineering clinically relevant design desire diabetes mellitus therapy diabetic genetically modified cells glycemic control immunoreactivity immunosuppressed improved in vivo innovation insulin secretion islet mathematical model multidisciplinary novel prevent programs response stem type I diabetic

项目摘要

DESCRIPTION (provided by applicant): A tissue engineered pancreatic substitute has the potential to provide a less invasive, more physiologic and potentially less costly regulation of blood glucose levels than current treatment methods based on insulin injections or insulin pumps. However, the development of tissue based therapies is hampered by the low availability of donor tissue and/or the need to immunosuppress the transplant recipient. Tissue substitutes based on non-pancreatic cells retrieved from the same patient and engineered for physiologically responsive insulin secretion have the potential to overcome both of these limitations. The long-range goal associated with this research program is to produce the fundamental knowledge and enabling technologies for developing an efficacious and immune acceptable tissue substitute based on such cells. The objective of this application is to engineer a pancreatic substitute consisting of two components: one, based on recombinant hepatic cells and the second, based on recombinant enteroendocrine cells. The central hypothesis is that these two components, in concert, exhibit insulin secretion dynamics closely approximating those of pancreatic islets and can restore normoglycemia more effectively than either component alone. Guided by strong preliminary data, the hypothesis will be addressed by the following three specific aims: 1) develop a pancreatic substitute based on recombinant hepatocytes secreting insulin under transcriptional regulation; 2) develop a substitute based on recombinant, insulin-secreting intestinal endocrine cells, which exhibit physiologic responsiveness at the secretion pathway level; 3) combine the constructs developed in Aims 1 and 2 to generate a substitute that exhibits appropriate insulin secretion dynamics for in vivo efficacy. The approach is innovative, as it engineers a functional tissue by combining two cell types with each providing a component of the desired functionality. The proposed research is significant, as it will generate new fundamental information on the development of autologous cell therapies for diabetes, which are not limited by tissue availability and immunoreactivity. It is expected that the generated knowledge will produce a significant advancement towards a therapy that is applicable at a clinically relevant scale.

描述（由申请人提供）：与基于胰岛素注射或胰岛素泵的当前治疗方法相比，组织工程的胰腺替代品有可能提供侵入性较小，更加生理和可能降低的血糖水平的成本调节。但是，基于组织的疗法的发展受到供体组织的可用性低和/或需要免疫抑制移植受者的需求。基于从同一患者中检索并为生理响应胰岛素分泌而设计的非胰细胞的组织替代物具有克服这两个局限性的潜力。与该研究计划相关的远程目标是生产基本知识和促进技术，以开发基于此类细胞的有效和免疫可接受的组织替代品。该应用的目的是设计由两个组成部分组成的胰腺替代品：一个基于重组肝细胞，第二个基于重组肠肠内分泌细胞。中心假设是，这两个组成部分在协同的情况下表现出胰岛素分泌动力学的近似于胰岛的胰岛素分泌动力学，并且可以比单独的任何一个分量更有效地恢复正常血糖。在强有力的初步数据的指导下，该假设将通过以下三个特定目的来解决：1）基于重组肝细胞在转录调节下分泌胰岛素的胰腺替代品； 2）基于重组，分泌肠内内分泌细胞的替代品，该细胞在分泌途径水平上表现出生理的反应性； 3）结合目标1和2中开发的构建体，以产生一种替代品，该替代品表现出适当的胰岛素分泌动力学，以实现体内功效。该方法是创新的，因为它通过将两种细胞类型与每种细胞类型相结合来设计功能组织，每种组织提供了所需功能的组成部分。拟议的研究很重要，因为它将生成有关糖尿病自体细胞疗法发展的新基本信息，这些信息不受组织可用性和免疫反应性的限制。预计生成的知识将在适用于临床相关规模的治疗方面产生重大进步。