Lipidomic, biophysical, and functional differentiation of Mesenchymal Stem Cell membranes

间充质干细胞膜的脂质组学、生物物理和功能分化

• 批准号: 9305122
• 负责人: Ilya Levental
• 金额: $ 36.28万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9305122
• 关键词: Address; Adipocytes; Affect; Alpha Cell; Alzheimer' s Disease; Animals; Autoimmunity; Bioinformatics; Biological; Biophysics; Cardiovascular Diseases; Cell Differentiation process; Cell Lineage; Cell membrane; Cell physiology; Cells; Cellular Membrane; Cholesterol; Data; Dementia; Development; Diabetes Mellitus; Diet; Dietary Factors; Dietary Fats; Disease; Docosahexaenoic Acids; Environment; Enzymatic Biochemistry; Eukaryotic Cell; Exogenous Factors; Family; Goals; Growth Factor Receptors; Health; Homeostasis; Human; Intake; Intervention; Investigation; Lateral; Length; Lipids; Malignant Neoplasms; Mass Spectrum Analysis; Measures; Mediating; Membrane; Membrane Lipids; Membrane Microdomains; Mesenchymal Differentiation; Mesenchymal Stem Cells; Methodology; Molecular; Monomeric GTP-Binding Proteins; Nature; Normal Cell; Omega-3 Fatty Acids; Osteoblasts; Osteoporosis; Output; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phenotype; Plasticizers; Predisposition; Property; Proteins; Regulation; Research; Risk Factors; Signal Transduction; Somatomedins; Structure; System; Testing; Time; Unsaturated Fats; Virus Diseases; analytical tool; biophysical properties; bone morphogenetic protein 2; disease phenotype; disorder risk; experimental study; fluidity; human disease; lipid metabolism; macromolecule; nervous system disorder; osteogenic; physical property; polyunsaturated fat; public health relevance; saturated fat; stem cell biology; tool; transmission process

DESCRIPTION (provided by applicant): Lipid membranes are the physical barriers and functional interfaces between cellular compartments, and are therefore involved in nearly every aspect of cellular physiology. To accommodate this exquisite functionality, membranes are composed of a vast array of lipids and proteins that self-organize on a variety of length and time scales. Disturbances to the lipid constituents of cellular membranes are associated with diverse disease phenotypes, including cardiovascular disease, autoimmunity, osteoporosis, neurological disorders, and cancer. Moreover, unique to lipids among other cellular macromolecules, lipid phenotypes can be affected directly by dietary lipid abundance and composition. Most notable are the deleterious health consequences associated with overconsumption of saturated and trans-unsaturated fats, and, conversely, the plethora of beneficial effects of ω-3 polyunsaturated fats (PUFA). Despite the broad significance of membrane phenotypes, the detailed lipid compositions determining these phenotypes, lipidomic remodeling during cellular processes, and the susceptibility of membrane composition and function to dietary lipid inputs have not been widely characterized. Recent analytic breakthroughs in holistic quantitation of membrane lipids have revealed that cells produce hundreds of distinct lipid species, and that cellular lipidomes are remarkably plastic, capable of rapid, large-scale, functional rearrangements. These observations prompt the hypothesis that both cell autonomous and exogenous factors drive membrane lipidome remodeling and that the resulting membrane phenotypes directly regulate cell function. To test this broad hypothesis, we propose a combination of mass spectrometry, membrane biophysics, and stem cell biology to characterize lipidomic and biophysical membrane remodeling during the differentiation of mesenchymal stem cells (MSCs), and how dietary lipids affect this remodeling to regulate MSC differentiation. In Aim 1, we will define the compositional and biophysical differentiation of whole membranes and isolated plasma membranes as MSCs undergo differentiation into adipocytes and osteoblasts. These observations will be combined with bioinformatic approaches to uncover the compositional determinants of physical properties in biological membranes. In Aim 2, we will extend these observations by investigating the modulation of membrane composition and physical properties by dietary lipids - specifically cholesterol, saturated / trans-unsaturated fats, and ω-3 PUFA. Further, we will evaluate the functional aspects of membrane remodeling by investigating the consequences of lipidomic disturbances on lineage-specific MSC differentiation. Finally, we will explore the molecular mechanisms behind these observations by the experiments proposed in Aim 3. We will dissect the mitogenic and differentiation pathways regulated by membrane remodeling to identify the molecules responsible for transducing membrane phenotypes into cellular signals. The long-term goal of this line of research is to identify modulators of membrane phenotypes for treatment of diseases associated with lipidomic perturbations and for promotion of desired cellular phenotypes, e.g. osteogenic differentiation of MSCs in osteoporosis.

描述（由申请人提供）：脂膜是细胞区室之间的物理屏障和功能界面，因此几乎涉及细胞生理学的各个方面。为了适应这种精致的功能，膜由大量的脂质和蛋白质组成，这些脂质和蛋白质在各种长度和时间尺度上自我组织。细胞膜脂质成分的紊乱与多种疾病表型相关，包括心血管疾病、自身免疫、骨质疏松症、神经系统疾病和癌症。此外，在其他细胞大分子中，脂质是唯一的，脂质表型可以直接受到膳食脂质丰度和组成的影响。最值得注意的是与饱和和反式不饱和脂肪的过度消费相关的有害健康后果，以及相反，ω-3多不饱和脂肪（PUFA）的过多有益作用。尽管膜表型的广泛意义，确定这些表型，lipidomic重塑在细胞过程中，和膜的组成和功能的易感性饮食脂质输入的详细脂质组合物尚未得到广泛的特点。最近在膜脂质的整体定量分析方面的突破表明，细胞产生数百种不同的脂质种类，并且细胞脂质体具有显著的可塑性，能够进行快速，大规模的功能性重排。这些观察提示细胞自主和外源性因素驱动膜脂质体重塑和由此产生的膜表型直接调节细胞功能的假设。为了验证这一广泛的假设，我们提出了一个质谱，膜生物物理学和干细胞生物学的组合来表征间充质干细胞（MSC）分化过程中的lipidomic和生物物理膜重塑，以及饮食脂质如何影响这种重塑来调节MSC分化。在目标1中，我们将定义整个膜和分离的质膜的组成和生物物理分化，因为MSC经历分化成脂肪细胞和成骨细胞。这些观察结果将与生物信息学方法相结合，以揭示生物膜物理特性的组成决定因素。在目标2中，我们将通过研究膳食脂质（特别是胆固醇、饱和/反式不饱和脂肪和ω-3 PUFA）对膜组成和物理性质的调节来扩展这些观察结果。此外，我们将通过研究脂质组学紊乱对谱系特异性MSC分化的影响来评估膜重塑的功能方面。最后，我们将通过目标3中提出的实验探索这些观察结果背后的分子机制。我们将剖析有丝分裂和分化途径调节膜重塑，以确定分子负责转导膜表型转化为细胞信号。这一系列研究的长期目标是鉴定膜表型的调节剂，用于治疗与脂质组学扰动相关的疾病和促进所需的细胞表型，例如骨质疏松症中MSC的成骨分化。