The Role of Ceramides in the Pancreatic Beta Cell

神经酰胺在胰腺β细胞中的作用

基本信息

批准号：
10467400
负责人：
WILLIAM L HOLLAND
金额：
$ 56.22万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10467400
关键词：
Adipose tissue Anabolism Animal Model Apoptosis Apoptotic Autoimmune Beta Cell Biological Assay Biological Markers Biotechnology Blood Glucose Carbohydrates Cell Survival Cell physiology Cells Ceramides Cessation of life Consumption Data Detergents Development Diabetes Mellitus Disease Drug Kinetics Enzymes Failure Family Fatty Acids Genes Glucose Growth Hormones Human Hyperglycemia Immunologics Impairment Inbred NOD Mice Inflammation Inflammatory Insulin Insulin-Dependent Diabetes Mellitus Intestinal permeability Islets of Langerhans Isotopes Lead Link Lipids Liver Macronutrients Nutrition Membrane Metabolic Metabolism Mitochondria Modeling Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Nutrient Nutritional Organism Pancreas Pathway interactions Pharmaceutical Preparations Pharmacodynamics Pharmacology Phenotype Population Production Property Rattus Rodent Rodent Model Role Safety Saturated Fatty Acids Science Signal Transduction Skeletal Muscle Solubility Sphingolipids Stress Structure of beta Cell of islet Testing Therapeutic Tissues Transgenic Mice Treatment Efficacy Work aqueous biological adaptation to stress cell regeneration cytokine detection of nutrient diabetic dihydroceramide dihydroceramide desaturase drug candidate efficacy testing impaired glucose tolerance improved in vivo inhibitor insulin secretion islet islet xenograft metabolomics mouse model novel novel therapeutics overexpression peptide hormone pi bond preservation prevent saturated fat single cell sequencing small molecule inhibitor theories therapeutic evaluation therapeutic target tool uptake

项目摘要

SUMMARY This proposal explores the hypothesis that sphingolipids such as ceramides serve as common, cell-autonomous signals that impair beta cell function and contribute to the development of type 1 and type 2 diabetes. The idea is predicated upon data presented herein showing that the administration of a pharmacological inhibitor of ceramide biosynthesis to rodents preserves the beta cell and prevents the development of both forms of the disease (i.e. in Zucker Diabetic Fatty rats as well as Non-Obese Diabetic mice). The theory is further supported by studies in human and mouse islets implicating ceramides as intermediates linking saturated fatty acids and inflammatory cytokines to the impairment of insulin secretion, mitochondrial function, and beta cell survival. We will evaluate this hypothesized role for ceramides and its metabolites in the pancreatic islet through the following aims: · First, we will study new mouse models allowing for the conditional, beta cell-specific modulation of genes involved in ceramide synthesis or degradation, allowing us to determine whether the lipids are either (a) necessary or (b) sufficient for beta cell failure and the onset of frank hyperglycemia. · Second, we will test the efficacy of a new class of ceramide synthesis inhibitors targeting dihydroceramide desaturase-1 as therapeutics that improve insulin secretion and prevent type 1 or type 2 diabetes in rodents. · Third, we will determine the mechanisms through which ceramides impair the function of mouse and human islets. We will test a hypothesized role for ceramides as drivers of metabolic reprogramming using state-of-the-art metabolic tracing, mitochondrial phenotyping, and cell function assays. Findings obtained from these studies could uncover new nutrient-sensing and/or inflammatory mechanisms that modulate islet function, survival and growth. Moreover, the translational component of this work could lead to the development of new therapeutic alternatives for preventing or treating diabetes.

概括该提案探讨了这样的假设：神经酰胺等鞘脂是常见的、细胞自主的损害 β 细胞功能并导致 1 型和 2 型糖尿病发展的信号。基于本文提供的数据，显示施用药物抑制剂啮齿类动物的神经酰胺生物合成可以保护 β 细胞并防止这两种形式的发育疾病（即 Zucker 糖尿病肥胖大鼠以及非肥胖糖尿病小鼠）该理论得到进一步支持。通过对人类和小鼠胰岛的研究表明神经酰胺是连接饱和脂肪酸和炎症细胞因子会损害胰岛素分泌、线粒体功能和β细胞存活。将通过以下方式评估神经酰胺及其代谢物在胰岛中的作用目标： · 首先，我们将研究新的小鼠模型，允许对基因进行有条件的、β细胞特异性的调节参与神经酰胺的合成或降解，使我们能够确定脂质是否是（a）对于 β 细胞衰竭和明显高血糖的发生是必要的或 (b) 足够的。 · 其次，我们将测试一类针对二氢神经酰胺的新型神经酰胺合成抑制剂的功效去饱和酶-1 作为改善胰岛素分泌并预防 1 型或 2 型糖尿病的治疗剂啮齿动物。 · 第三，我们将确定神经酰胺损害小鼠和小鼠功能的机制我们将使用神经酰胺作为代谢重编程驱动因素来测试其先锋作用。最先进的代谢追踪、线粒体表型分析和细胞功能测定。从这些研究中获得的结果可能会揭示新的营养感知和/或炎症机制，此外，这项工作的翻译部分可能会导致胰岛功能、存活和生长。开发预防或治疗糖尿病的新治疗替代品。