The Unfolded Protein Response in Sterol Cytotoxicity

甾醇细胞毒性中未折叠的蛋白质反应

基本信息

批准号：
7158569
负责人：
Ira A Tabas
金额：
$ 38.76万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-12-01 至 2008-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7158569
关键词：
Acute Affect Apical Apolipoprotein E Apolipoproteins B Apoptosis Apoptotic Arterial Fatty Streak Atherosclerosis Biliary Binding Blood Vessels Ca(2+)-Transporting ATPase Calcium Calcium Channel Cell physiology Cells Cessation of life Cholesterol Chylomicrons Clinical Complex Data Dietary Cholesterol Disease Disruption Distal Endoplasmic Reticulum Enzymes Epithelial Epithelial Cells Event Exposure to Functional disorder Gastrointestinal tract structure Genes Goals In Vitro Induction of Apoptosis Intestines Lesion Life Lipids Localized Mediating Membrane Metabolism Modeling Molecular Mus Myocardial Infarction Necrosis Pathway interactions Phosphotransferases Physiology Phytosterols Play Predisposition Process Protein Kinase Proteins Resistance Role Ryanodine Receptor Calcium Release Channel Signal Transduction Pathway Sterol O-Acyltransferase Sterols Stress Testing Toxic effect apolipoprotein B-48 base cholesterol trafficking cytotoxic cytotoxicity dietary excess feeding in vivo inhibitor/antagonist inositol-1,4,5-triphosphate receptor interest intestinal epithelium macrophage mouse model novel novel therapeutics null mutation prevent reconstitution research study response sterol O-acyltransferase 1 sterol O-acyltransferase 2 therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The responses of cells to high levels of sterols has important implications for disease processes and normal physiology. In one setting, the accumulation of free cholesterol (FC) by atheroma macrophages (Mfs) leads to Mf death, which likely promotes plaque instability and acute clinical events, like myocardial infarction. In another setting, intestinal epithelial cells (IECs) are exposed to high levels of potentially toxic dietary and biliary cholesterol and dietary plant sterols, and so mechanisms are necessary to prevent intestinal dysfunction. The PI has recently discovered that a complex signal transduction pathway in the endoplasmic reticulum (ER)--the Unfolded Protein Response (UPR)--plays a critical role in the response of cultured Mrs to FC. The UPR first triggers a set of adaptive response, but then induces apoptosis if the adaptive responses fail. As such, the UPR initially promotes survival in FC-Ioaded Mfs, but then promotes apoptosis after prolonged FC loading. Because a unique branch of the UPR is localized to the gastrointestinal tract, and because a critical enzyme that protects IECs from sterol cytotoxicity is induced by the UPR, the UPR may also play an important role in the protection of IECs from high levels of sterols. In this context, the overall objective of this proposal is to investigate the roles and mechanisms of the UPR in adaptive and pathophysiological processes associated with the accumulation of excess sterols by atheroma Mfs and IECs. This objective will be met by: (a) determining if null mutations in two key UPR genes--one involved in the adaptive response and the other in apoptosis--affect lesional Mf death and plaque instability in the apoE-/- mouse model of atherosclerosis; (b) determining if the UPR is induced in IECs of mice exposed to excess dietary and plant sterols; if proteins known to help protect IECs from sterols are induced by the UPR; and if disruption of the UPR leads to intestinal dysfunction; and (c) investigating how FC induces the UPR by testing the hypothesis that FC enrichment of the ER membrane depletes ER calcium, which is a well-known and potent inducer of the UPR, by inhibiting the sarco/endoplasmic reticulum calcium ATPase or by activating ER calcium channels. The Mf studies will add to our understanding of how plaques become vulnerable and will suggest novel therapeutic targets involved in acute vascular events, and the intestinal studies will reveal a new and important aspect of intestinal-sterol physiology.

描述（由申请人提供）：细胞对高固醇的反应对疾病过程和正常生理学具有重要意义。在一种情况下，动脉粥样硬化巨噬细胞（MFS）的游离胆固醇（FC）积累会导致MF死亡，这可能会促进斑块不稳定性和急性临床事件，例如心肌梗塞。在另一种情况下，肠上皮细胞（IEC）暴露于高水平的潜在毒性饮食和胆汁胆固醇和饮食植物固醇中，因此需要机制来防止肠道功能障碍。 PI最近发现，内质网（ER）中的复杂信号转导途径 - 未折叠的蛋白质反应（UPR） - 在培养的MRS对FC的响应中起着至关重要的作用。 UPR首先会触发一组自适应反应，但如果自适应反应失败，则会诱导凋亡。因此，UPR最初促进了FC iioaded MFS的存活率，但随后在长时间的FC负载后促进了凋亡。由于UPR的独特分支位于胃肠道，并且由于UPR诱导了保护IEC免受固醇细胞毒性的关键酶，因此UPR也可能在保护IEC免受高含量的IEC保护中起重要作用。在这种情况下，该提案的总体目的是研究UPR在适应性和病理生理过程中与动脉瘤MFS和IEC相关的过量固醇相关的作用和机制。该目标将通过：（a）确定两个关键的UPR基因中的零突变（一个参与自适应反应，另一个参与凋亡）是否会影响动脉粥样硬化的ApoE - / - 小鼠模型中的病变MF死亡和斑块不稳定；（b）确定在暴露于过量饮食和植物固醇的小鼠的IEC中是否诱导了UPR；如果已知可以帮助保护IEC免受固醇的蛋白质由UPR诱导；如果UPR的破坏会导致肠功能障碍；（c）通过检验以下假设来研究FC如何通过抑制SARCO/内质网钙钙ATPase或通过激活Ercium calcium Mannels来抑制sarco/sarco/toplim canterels的假设，即ER膜的富集耗尽ER的ER钙。 MF研究将增加我们对斑块如何变得脆弱的理解，并建议参与急性血管事件的新型治疗靶标，并且肠道研究将揭示肠道生理学的新的重要方面。