Matrix assisted cell transplantation of brown fat

基质辅助棕色脂肪细胞移植

• 批准号: 9304213
• 负责人: KEVIN Edward HEALY
• 金额: $ 41.95万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-06 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9304213
• 关键词: Adhesions; Adipose tissue; Adrenergic Agents; Adult; Affect; Animals; Autologous; Autologous Transplantation; Basal metabolic rate; 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; Hormones; Hyaluronic Acid; Hydrogels; Implant; In Vitro; Injectable; Injection of therapeutic agent; Lead; Ligands; Lipoproteins; Liver diseases; Location; Maintenance; Mesenchymal Stem Cells; Metabolic; Metabolic Control; Metabolism; Methods; Mitochondria; Modulus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Performance; Pharmacologic Substance; Pharmacology; Phenotype; Process; Respiration; Rest; Risk; Running; Serum; Signal Transduction; Site; Source; System; Testing; Thermogenesis; Tissue Differentiation; Tissue Engineering; Tissue Expansion; Tissue-Specific Gene Expression; Tissues; Transgenes; Translating; Weight; Work; adipokines; base; cellular transduction; combat; design; experimental study; falls; food consumption; gene therapy; glucose tolerance; implantation; in vivo; insulin sensitivity; insulin tolerance; interdisciplinary approach; interest; metabolic rate; novel; novel strategies; obesity treatment; pre-clinical; public health relevance; uptake

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）具有在称为非颤抖性产热的过程中将代谢能作为热量耗散的固有能力，因此可以将其自身用于新型抗肥胖治疗方法。扩大BAT的策略分为两大类，药物/遗传干预，以触发内源性BAT分化途径或体外生成/扩大棕色脂肪，然后植入。由于可能驱动白色脂肪组织（WAT）向BAT转变或WAT的“布朗宁”的分化途径的药理学活化存在影响其他组织的分化和功能的风险，并且对分化的位置和程度提供不良的控制。 BAT的扩张，我们将侧重于后一种方式。我们在斯塔尔和希利实验室之间合作的总体战略将是利用水凝胶生物工程和代谢生物学方面的专业知识来证明BAT基础抗肥胖策略的可行性，该策略可以很容易地从临床前阶段转化为实际应用。这里的中心假设是，可以利用代谢生物学和组织工程的多学科方法来开发自体移植方法，以扩大BAT质量和静息能量消耗，以对抗肥胖相关疾病，如2型糖尿病和脂肪肝。我们的方法将侧重于：1）利用WAT作为间充质干细胞（MSC）的容易获得的来源，并通过将可溶性信号传导因子与优化的粘附配体组合来优化BAT分化条件，而不引入转基因; 3）用已经离体测试的基质进行体内实验，以进一步优化体内性能，特别关注于确定组织持久性、BAT表型的维持、细胞能量学和作为基质组成、生长因子和植入位点的函数的整个动物代谢;和4）证明优化的BAT-MACT确实可以用作有效的抗肥胖方法并促进肥胖相关疾病的保护和逆转。

项目成果

Molecular weight and concentration of heparin in hyaluronic acid-based matrices modulates growth factor retention kinetics and stem cell fate.

• DOI: 10.1016/j.jconrel.2015.04.034
• 发表时间: 2015-07-10
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Jha AK;Mathur A;Svedlund FL;Ye J;Yeghiazarians Y;Healy KE
• 通讯作者: Healy KE