Alleviating lysosomal lipid defects in ADRD by blocking cholesterol storage

通过阻断胆固醇储存来缓解 ADRD 中的溶酶体脂质缺陷

• 批准号: 10187943
• 负责人: Ta Yuan CHANG
• 金额: $ 40.84万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10187943
• 关键词: 3-Dimensional; Acyl Coenzyme A; Administrative Supplement; Alleles; Alzheimer' s disease related dementia; Animal Model; Apolipoprotein E; Atherosclerosis; Blood - brain barrier anatomy; Brain; Cells; Cholesterol; Cholesterol Esters; Cholesterol Homeostasis; Clinical; Complex; Defect; Dementia; Diabetes Mellitus; Diet; Disease; Dyslipidemias; Enzymes; Etiology; Goals; Intraperitoneal Injections; Laboratories; Lipids; Lipoprotein (a); Microglia; Minor; Modeling; Mus; Neurodegenerative Disorders; Neurons; Obesity; Outcome; Permeability; Protein Isoforms; Serum; Smooth Muscle Myocytes; Sterol O-Acyltransferase; Stroke; Testing; Therapeutic; Vascular Dementia; apolipoprotein E-3; apolipoprotein E-4; base; brain cell; drug candidate; drug testing; efficacy testing; genetic risk factor; inhibitor/antagonist; macrophage; men; mouse model; nanoparticle; parent grant; pre-clinical; small molecule; western diet

ABSTRACT of the administrative supplement proposal for the parent grant “Alleviating lysosomal lipid defects in ADRD by blocking cholesterol storage” The long-term goal of this laboratory is to produce cholesterol metabolism-based therapeutics to treat AD and ADRDs. Vascular dementia (VaD), an ADRD, is the second most common form of dementia after AD in the US. The etiology of VaD is complex, but is closely associated with dyslipidemia, atherosclerosis, stroke, and diabetes. Atherosclerosis is characterized by accumulation of cholesterol, cholesteryl esters and other lipids in macrophages and smooth muscle cells within the arterial walls. Acyl coenzyme A: cholesterol acyltransferase 1 (ACAT1) is an enzyme that converts cholesterol to cholesterol esters for storage in all cells, including macrophages, smooth muscle cells, as well as microglia and neurons in the brain. Our laboratory has been working on ACAT1 for several decades. We and others demonstrated that in mouse models, inhibiting ACAT1 benefit several diseases, including atherosclerosis, diet induced obesity, and AD. ApoE is a lipoprotein that transports cholesterol and other lipids in the body and in the brain. Apoe3 is the major allele. Apoe4, a minor allele, is a major genetic risk factor for AD; it is also a genetic risk factor for stroke associated VaD. It is desirable to produce animal models that partially recapitulate the essential features of VaD, such that candidate drug(s) can be tested at the preclinical level. However, at present, no mouse model for atherosclerosis associated VaD in ApoE isoform specific manner is available. To begin to fill this void, in the supplement request, we propose to produce such a model, and we refer it as the Athero/E3 and Athero/E4 mice. Compound F is a clinically approved small molecule ACAT1 inhibitor, originally intended to treat atherosclerosis, but was abandoned because compound F was not as efficient as statin in reducing serum cholesterol levels in men. Whether F was permeable to blood brain barrier was unknown. We have developed a nanoparticle platform and showed that F present in this nanoparticle is permeable to blood brain barrier. We have also shown that after IP injections to mice, nanoparticle F efficiently inhibited ACAT1 in body cells and in brain cells. In the supplement request, we propose to use nanoparticle F to treat the Athero/E3 and Athero/E4 mice under Western diet.

父母赠款的行政补充提案摘要 “通过阻止胆固醇储存来减轻ADRD的溶酶体脂质缺陷” 该实验室的长期目标是生产基于胆固醇代谢的治疗 治疗广告和ADRD。血管性痴呆（VAD）是ADRD，是第二个最常见的形式 在美国广告后的痴呆症。 VAD的病因很复杂，但与 血脂血症，动脉粥样硬化，中风和糖尿病。动脉粥样硬化的特征是 胆固醇，胆固醇酯和巨噬细胞中其他脂质的积累 动脉壁内的细胞。酰基辅酶A：胆固醇酰基转移酶1（ACAT1）是一种酶 这将胆固醇转换为胆固醇酯以存储在所有细胞中，包括巨噬细胞，光滑 肌肉细胞以及大脑中的小胶质细胞和神经元。我们的实验室一直在研究 ACAT1数十年。我们和其他人证明，在小鼠模型中，抑制ACAT1 受益几种疾病，包括动脉粥样硬化，饮食诱发的肥胖和AD。 APOE是一种脂蛋白，可在体内和大脑中输送胆固醇和其他脂质。 APOE3 是主要的等位基因。 APOE4是次要等位基因，是AD的主要遗传危险因素。这也是一种遗传风险 中风相关VAD的因素。希望产生部分概括的动物模型 VAD的基本特征，使候选药物可以在临床前测试。 但是，目前尚无针对ApoE同工型中的动脉粥样硬化的小鼠模型 具体方式可用。为了开始填补这一空白，在补充请求中，我们建议 产生这样的模型，我们将其称为Athero/E3和Athero/E4小鼠。 化合物F是经临床批准的小分子ACAT1抑制剂，最初旨在治疗 动脉粥样硬化，但被放弃了，因为化合物F在减少方面不如他汀类药物高效 男性血清胆固醇水平。 F是否可以渗透到血脑屏障上是未知的。我们 已经开发了一个纳米颗粒平台，并表明该纳米颗粒中存在的F是可渗透的 到血脑屏障。我们还表明，在对小鼠注射IP后，有效地注射纳米颗粒F 抑制身体细胞和脑细胞中的ACAT1。在补充要求中，我们建议使用 纳米颗粒F在西方饮食下处理Athero/e3和Athero/e4小鼠。