Molecular Profiling of Pancreatic Pathophysiology by Imaging Mass Spectrometry

通过成像质谱法对胰腺病理生理学进行分子分析

• 批准号: 8908974
• 负责人: Boone M. Prentice
• 金额: $ 5.24万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-22 至 2016-07-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8908974
• 关键词: Adolescent; Adult; Affect; Alpha Cell; Amputation; Anatomy; Antibodies; Arachidonic Acids; Architecture; Beta Cell; Biochemical; Biological; Biological Markers; Biology; Blindness; Cell Death; Cells; Cellular Structures; Ceramides; Cessation of life; Chemistry; Collaborations; Complex; Development; Diabetes Mellitus; Diagnosis; Disease; Disease Progression; Endocrine; Environment; Functional disorder; Future; Goals; Health; Heart Diseases; Homeostasis; Hormones; Human; Hypertension; Image; Imaging technology; Immunohistochemistry; In Situ; Insulin Resistance; Interdisciplinary Study; Islet Cell; Islets of Langerhans; Kidney Diseases; Knowledge; Leptin; Lipids; Location; Longitudinal Studies; Maps; Mass Spectrum Analysis; Measurement; Measures; Medical; Metabolic; Metabolism; Methods; Molecular; Molecular Profiling; Morphology; Mus; Nature; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Organogenesis; Pancreas; Pathway interactions; Phospholipids; Play; Population; Process; Productivity; Proteins; Research; Resolution; Role; Scientist; Signal Pathway; Signal Transduction; Signaling Molecule; Specimen; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Staging; Stroke; Sulfoglycosphingolipids; Techniques; Technology; Testing; Tissues; Training; Translating; United States; base; blood glucose regulation; career; cell type; cost; design; diabetic; endocrine pancreas development; glucose transport; insight; interdisciplinary approach; interest; islet; lipid metabolism; loss of function; molecular array; molecular imaging; mouse model; novel; novel strategies; outcome forecast; post-doctoral training; public health relevance; therapeutic target

 DESCRIPTION (provided by applicant): While hormone-secreting pancreatic islet cells (e.g.,  cells and ß cells) have been identified to play key roles in glucose homeostasis, our understanding of the processes important to normal pancreatic organogenesis and leading to altered metabolic states such as type 2 diabetes (T2D) is still limited. The low availability of human islets and the lack of experimental methods to comprehensively analyze islet cells and their tissue environments restrict our ability to map cell signaling pathways and metabolism. Despite substantial progress towards treatments and cures, much remains unknown about the specific signaling and damage pathways that contribute to ß-cell dysfunction. A more fundamental understanding of islet development and diabetes pathophysiology is required to help direct diagnoses, prognoses, treatments, and therapies and likely begins at the molecular level. In this way, novel biochemical understandings can be translated to insights on pancreatic development and disease progression, ultimately leading to the identification of new potential biomarkers and therapeutic targets. The proposed discovery-based research herein will provide molecular-level insight on pancreatic islet architecture, function, and development by combining a form of new molecular imaging technology, matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS), with existing validated approaches. This technology is well suited to measuring the complex array of molecular information (e.g., lipids and proteins) present in cellular tissue and provides for an untargeted measurement method, which is ideal for the discovery of new molecules important to pancreatic function. We aim to utilize such in situ tissue-based IMS techniques to develop much more complete molecular maps for the different pancreatic endocrine cell types, allowing us to gain insight as to the cell signaling pathways involved in pancreatic development and disease progression. These IMS techniques will be used to specifically define the lipid and protein molecular signatures of normal mouse islets and correlate these maps to functional changes observed in the presence of obesity and insulin resistance. This will allow us to establish those lipid and protein signaling molecules crucial to lipotoxicity and islet dysfunction in the well-studied ob/ob mouse model. Finally, these IMS approaches will be expanded to perform a longitudinal study identifying differences in protein and lipid profiles of human pancreatic islet cells throughout organogenetic development from the juvenile to the adult stages, and determining how these biochemical changes relate to morphological and architectural changes in the tissue. The molecular profiles produced by these interdisciplinary studies will provide insights on the cell signaling mechanisms important in pancreatic maturation and disease progression and will aid in the design of novel therapies and strategies to sustain islet mass and function.