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Matrix assisted cell transplantation of brown fat

基质辅助棕色脂肪细胞移植

基本信息

批准号：
8776672
负责人：
KEVIN Edward HEALY
金额：
$ 41.82万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
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：
2014-09-06 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8776672
关键词：
Adhesions Adipose tissue Adult Affect Animals Autologous Autologous Transplantation Basal metabolic rate Binding Biological Assay Biology Biomedical Engineering Body Temperature Body Weight decreased Brown Fat Calories Categories Cell Count Cell Respiration Cell Separation Cell Transplantation Cell Transplants Cells Characteristics Collaborations Data Development Diabetes Mellitus Diet Disease Energy Metabolism Engineering Fatty Acids Fatty Liver Generations Genetic Models Glucose Goals Growth Factor Heating Histocompatibility Testing Hormones Hyaluronic Acid Hydrogels Implant In Vitro Injection of therapeutic agent Lead Ligands Lipoproteins Liver diseases Location Maintenance Mesenchymal Stem Cells Metabolic Metabolic Control Metabolism Methods Mitochondria Non-Insulin-Dependent Diabetes Mellitus Obesity Pathway interactions Performance Pharmacologic Substance Phenotype Process Reading Respiration Rest Risk Running Serum Signal Transduction Site Source Staging System Testing Thermogenesis Tissue Differentiation Tissue Engineering Tissue Expansion Tissue-Specific Gene Expression Tissues Transgenes Translating Weight Work base cellular transduction combat design falls food consumption gene therapy glucose tolerance implantation in vivo insulin sensitivity insulin tolerance interdisciplinary approach interest novel novel strategies obesity treatment pre-clinical public health relevance research study uptake

项目摘要

DESCRIPTION (provided by applicant): Brown adipose tissue (BAT) possesses the inherent ability to dissipate metabolic energy as heat in a process termed non-shivering thermogenesis and thus could lend itself to novel anti-obesity treatment approaches. Strategies for expanding BAT fall into two general categories, pharmaceutical/genetic intervention to trigger endogenous BAT differentiation pathways or ex vivo generation/expansion of brown fat followed by implantation. Since pharmacological activation of differentiation pathways that might drive a white adipose tissue (WAT) to BAT transition, or "browning" of WAT, runs the risks of affecting differentiation and function of other tissues and offers poor control of the location and extend of BAT expansion, we will focus on the latter approach. Our overall strategy in this collaboration between the Stahl and Healy labs will be to leverage expertise in bioengineering of hydrogels and in metabolic biology to demonstrate the feasibility of a BAT base anti-obesity strategy that could be readily translated from the pre-clinical stage to actual application. The central hypothesis here is that a multidisciplinary approach of metabolic biology and tissue engineering can be utilized to develop an autologous transplantation approach to expand BAT mass and resting energy expenditure to combat obesity-associated disorders such as type-2 diabetes and hepatosteatosis. Our approach will focus on: 1) utilizing WAT as a readily available source of mesenchymal stem cells (MSC) and to optimize BAT differentiation conditions, without the introduction of transgenes, by combining soluble signaling factors with optimized adhesion ligands; 2) development of 3D matrixes composed of bio-inspired hyaluronic acid (HyA) hydrogels that can be designed to enhance the differentiation of WAT-derived MSCs into BAT; 3) to perform in vivo experiments with matrixes that have been tested ex vivo to further optimize for in vivo performance with a specific focus on determining tissue persistence, maintenance of BAT phenotype, cellular energetics, and whole animal metabolism as a function of matrix composition, growth factors, and implantation site; and 4) to demonstrate that optimized BAT-MACTs can indeed be used as a potent anti-obesity approach and facilitate the protection and reversal of obesity associated disorders.

描述（由申请人提供）：棕色脂肪组织（BAT）具有将代谢能量作为热量在称为非寒颤产热过程中消散的固有能力，因此可以使其成为新的抗肥胖治疗方法。扩大BAT的策略可分为两大类：通过药物/基因干预触发内源性BAT分化途径，或体外生成/扩增棕色脂肪，然后植入。由于分化途径的药理激活可能会驱动白色脂肪组织（WAT）向BAT转变，或WAT的“褐变”，有影响其他组织分化和功能的风险，并且对其位置和延伸的控制很差