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Microsomal Transfer Protein Modulates Lipoprotein Metabolism and Retinal lipid Homeostasis

微粒体转移蛋白调节脂蛋白代谢和视网膜脂质稳态

基本信息

批准号：
10372593
负责人：
Kathleen Boesze-Battaglia
金额：
$ 25.49万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2022-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10372593
关键词：
ATP binding cassette transporter 1 Ablation Acids Address Aging Apical Apolipoproteins Apolipoproteins B Blindness Bruch&apos s basal membrane structure Cardiac Myocytes Cell Culture System Cell Culture Techniques Cell physiology Cells Characteristics Cholesterol Cholesterol Homeostasis Choroid Complex Consequentialism Deposition Development Disease Endoplasmic Reticulum Energy-Generating Resources Enterocytes Equilibrium Fatty Acids Foundations Functional disorder Gatekeeping Genes Genetic Health Hepatocyte Homeostasis Human Inflammation Inflammatory Inflammatory Response Ingestion Intracellular Accumulation of Lipids Lead Lesion Lipids Lipoproteins Liver Low-Density Lipoproteins Mediating Metabolic Metabolism Missense Mutation Mitotic Morphology Mouse Protein Neural Retina Pathologic Pathway interactions Patients Phagocytosis Pharmacology Plasma Play Process Production Protein Deficiency Proteins Recycling Regulation Retina Retinal Degeneration Retinal Diseases Retinal Pigments Role Secondary to Structure of retinal pigment epithelium System Testing Toxic effect Vision age related cholesterol transporters density environmental stressor human fetal retinal pigment epithelial cell in vivo induced pluripotent stem cell lipid metabolism lipid transfer protein mouse model negative affect normal aging novel oxidation prevent protein function western diet

项目摘要

Lipid handling is one of the most critical functions of the retinal pigment epithelium (RPE) a single mitotically inactive cell layer that is situated between the neural retina and the Bruch's membrane-Choroid. Visual function depends on the intimate structural, functional and metabolic interactions between the RPE and the neural retina. Within this complex, lipid metabolism is tightly regulated, and its' dysregulation triggers accumulation of excess lipids within the RPE and the adjacent Bruch's membrane and choroidal vasculature. In the human retina the accumulation of neutral lipid deposits is a characteristic of aging and precedes disease associated-lesions. A signiﬁcant proportion of this neutral lipid is enclosed within apolipoprotein B100 containing lipoproteins (Blps) that resemble cardiomyocyte associated Blps. The prodigious amount of lipid that must be processed by the RPE, through the recycling and metabolism of lipid rich outer segments and ingestion of circulating lipoproteins, predicts that to prevent lipid overload the RPE synthesize and secrete Blp. In this regard, RPE shares metabolic similarity with cardiomyocytes; both utilize fatty acids as an energy source and both secrete unique EC rich Blps. While it has been shown that MTP-mediated secretion of Blps protects cardiomyocytes from lipid accumulation, there is a paucity of studies regarding Blp assembly/secretion by RPE in vivo. In these studies we will use mouse models and cell culture to decipher the pathological consequences associated with dysregulation of Blp assembly and secretion pathway by inhibiting or genetic ablation of the Mttp gene in RPE. Microsomal transfer protein (MTP), the product of the MTTP gene, is an endoplasmic reticulum-resident lipid transfer protein necessary for Blp assembly and secretion. In the first specific aim we will test the hypothesis that MTP-mediated secretion of Blp is a mechanism for protecting against RPE lipid overload. To test the contribution of localized synthesis and secretion of Blp by the RPE to retinal lipid homeostasis and cell function in a metabolically intact system, we generated the RPE-specific MTP deficient (RPEMttp) mouse. In the second specific aim we will test the hypothesis that Blp assembly is modulated by the daily load of ingested OS lipids. We will use RPE differentiated from human induced pluripotent stem cells (iPSCs) to investigate the mechanism by which lipids taken up through outer segment phagocytosis regulate MTP activity and Blp production. Using these cells, we will determine if loss of MTP, either through gene ablation (KD of MTP in iRPE) or pharmacological inhibition, contributes to RPE steatosis. Collectively, these exploratory studies will address the specific role of local Blp assembly in retinal lipid homeostasis. Dysregulation of Blp function can cause non- autonomous changes that negatively affect the entire system and lead to vision loss. These studies maybe foundational to study subsequent steps in the development of age-related changes such as inflammation and degeneration associated with dysregulation of lipoprotein metabolism.

脂质处理是视网膜色素上皮（RPE）单一有丝分裂过程中最关键的功能之一