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Apolipoprotein conformation in amyloid and cardiovascular diseases

淀粉样蛋白和心血管疾病中的载脂蛋白构象

基本信息

批准号：
10918498
负责人：
Olga Gursky
金额：
$ 12.48万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-12-15 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10918498
关键词：
Acceleration Address Affect Affinity Affinity Chromatography Aftercare Alzheimer&apos s Disease American Amyloid Amyloid deposition Amyloidosis Apolipoprotein A-I Apolipoprotein A-II Apolipoprotein E Apolipoproteins Apolipoproteins B Atherosclerosis Binding Biochemical Biological Markers Biological Models Biophysics Books COVID-19 mortality Cardiovascular Diseases Cardiovascular system Cartoons Cell Nucleus Cells Cessation of life Cholesterol Chronic Complement Complex Complication Computing Methodologies Data Set Deposition Deuterium Diagnosis Disease Disease Management Goals Heparin Heparin Binding Heparitin Sulfate High Density Lipoproteins Human Hydrogen In Vitro Inflammation Kinetics Life Link Lipids Lipolysis Lipoprotein (a)Lipoproteins Low-Density Lipoproteins Mass Spectrum Analysis Measures Metabolic Metabolism Minor Modeling Molecular Molecular Conformation Morbid Obesity Non-Insulin-Dependent Diabetes Mellitus Obesity Outcome Particle Size Pathway interactions Patients Periodicals Peripheral Pilot Projects Plasma Population Process Progress Reports Property Proteins Public Health Publications Receptor Cell Research Role Serum amyloid A protein Structure Surface Testing Triglycerides Very low density lipoprotein Virus Diseases Work amyloid formation bariatric surgery biochemical tools biophysical tools computerized tools crosslink diagnostic tool disorder risk extracellular fundamental research in vivo lipid metabolism lipoprotein lipase lipoprotein triglyceride mimetics nanoparticle novel novel diagnostics novel marker obese patients obese person obesity biomarkers obesity treatment particle premature protein misfolding severe COVID-19 stem therapeutic target tissue tropism

项目摘要

Abstract Aberrant lipoprotein metabolism is a hallmark of obesity that affects >40% of Americans. Obesity and its com- plications, including type-2 diabetes (T2D), cardiovascular, amyloid and severe viral diseases, are the leading causes of premature death. The ultimate goal of this research is to help diagnose and treat these disorders. This project addresses critical unresolved questions in the lipoprotein functionality in obesity. High-, low- and very low- density lipoproteins (HDL, LDL and VLDL) are diverse nanoparticles comprised of lipids and apolipoproteins that direct lipid metabolism in plasma. This process is extremely complex and many details are unknown. Our current focus is on the interactions of lipoproteins and proteins with heparan sulfate (HS), which can trigger both cardio- vascular and amyloid diseases. We will determine the molecular mechanisms of apolipoprotein-HS interactions and altered lipoprotein functionality in obesity. Our powerful approach, which integrates a wide array of biochem- ical, biophysical and computational tools, enabled us to postulate compelling new hypotheses that will be tested in three complementary specific aims. Aim 1 will determine how lipoprotein functionality changes in obesity be- fore and after treatment. Lipoproteins from healthy and morbidly obese subjects will be isolated based on the heparin binding affinity, and their biochemical and functional properties will be determined. Our new hypothesis supported by strong pilot studies will be tested: small particles formed upon action of lipoprotein lipase on circu- lating VLDL provide novel biomarkers of obesity and readouts for treatment. Aim 2 will define the biochemical and functional details of serum amyloid A (SAA) transfer from HDL to LDL in obesity. Our pilot studies indicate that transfer of this small protein induces pro-atherogenic changes in LDL, and suggest two hypotheses that will be tested: i) new mechanistic links between obesity, elevated SAA and atherosclerosis, and ii) novel beneficial role of SAA as a lipid scavenger in obesity. Aim 3 will determine how HS and heparin affect SAA misfolding in amyloid A (AA) amyloidosis, a life-threatening complication of obesity and chronic inflammation. SAA binding to HS is a therapeutic target in AA amyloidosis but molecular details are lacking. Our pilot studies suggest that: i) SAA binding to HS initiates an extracellular pathway of amyloid deposition; ii) periodic anionic arrays in HS bind to stacks of basic residues in amyloid and stabilize amyloid nuclei. To test these intriguing new ideas, we will combine biochemical, biophysical, hydrogen-deuterium exchange mass spectrometry, and computational meth- ods with atomic structures of SAA in crystals and fibrils. Outcome: this research will identify new mechanistic links between obesity and atherosclerosis; verify the hypothetical vital role of SAA as a lipid scavenger; clarify its misfolding pathway in amyloid; and help develop new diagnostic tools and treatments for obesity and related disorders. Broader impact of this research is that it will: i) help understand and modulate the causal link between obesity, T2D and severe COVID-19 disease, and ii) uncover the molecular underpinnings of HS-amyloid inter- actions that can critically impact not only in AA but also Alzheimer's and other major amyloid diseases.

抽象的脂蛋白代谢异常是肥胖的一个标志，影响超过 40% 的美国人。肥胖及其并发症并发症，包括 2 型糖尿病 (T2D)、心血管疾病、淀粉样蛋白疾病和严重病毒性疾病，是主要的并发症过早死亡的原因。这项研究的最终目标是帮助诊断和治疗这些疾病。这该项目解决了肥胖中脂蛋白功能方面尚未解决的关键问题。高、低和极低密度脂蛋白（HDL、LDL 和 VLDL）是由脂质和载脂蛋白组成的多种纳米颗粒，血浆中的直接脂质代谢。这个过程极其复杂，很多细节都是未知的。我们目前的重点是脂蛋白和蛋白质与硫酸乙酰肝素 (HS) 的相互作用，这可以触发心脏血管和淀粉样蛋白疾病。我们将确定载脂蛋白-HS相互作用的分子机制并改变肥胖中的脂蛋白功能。我们强大的方法整合了广泛的生物化学- 科学、生物物理和计算工具使我们能够提出令人信服的新假设并进行测试三个互补的具体目标。目标 1 将确定肥胖中脂蛋白功能如何变化治疗前和治疗后。来自健康和病态肥胖受试者的脂蛋白将根据肝素结合亲和力及其生化和功能特性将被确定。我们的新假设将在强有力的试点研究的支持下进行测试：脂蛋白脂肪酶作用于循环系统时形成的小颗粒相关 VLDL 提供了新的肥胖生物标志物和治疗读数。目标 2 将定义生化以及肥胖症中血清淀粉样蛋白 A (SAA) 从 HDL 转移到 LDL 的功能细节。我们的试点研究表明这种小蛋白质的转移会引起 LDL 中促动脉粥样硬化的变化，并提出了两个假设进行测试：i) 肥胖、SAA 升高和动脉粥样硬化之间的新机制联系，以及 ii) 新的有益作用 SAA 作为脂质清除剂在肥胖中的作用。目标 3 将确定 HS 和肝素如何影响 SAA 错误折叠淀粉样蛋白 A (AA) 淀粉样变性，一种肥胖和慢性炎症的危及生命的并发症。 SAA 绑定到 HS 是 AA 淀粉样变性的治疗靶点，但缺乏分子细节。我们的试点研究表明：i) SAA 与 HS 结合启动淀粉样蛋白沉积的细胞外途径； ii) HS 结合中的周期性阴离子阵列淀粉样蛋白中碱性残基的堆积并稳定淀粉样蛋白核。为了测试这些有趣的新想法，我们将结合生物化学、生物物理、氢-氘交换质谱和计算方法晶体和原纤维中具有 SAA 原子结构的 ods。结果：这项研究将确定新的机制肥胖与动脉粥样硬化之间的联系；验证 SAA 作为脂质清除剂的假设重要作用；阐明淀粉样蛋白中的错误折叠途径；并帮助开发针对肥胖及相关疾病的新诊断工具和治疗方法失调。这项研究的更广泛影响在于：i) 帮助理解和调节之间的因果关系肥胖、T2D 和严重的 COVID-19 疾病，以及 ii) 揭示 HS-淀粉样蛋白间质的分子基础这些行动不仅对 AA 产生严重影响，而且对阿尔茨海默病和其他主要淀粉样蛋白疾病产生严重影响。