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

• 批准号: 10475835
• 负责人: Olga Gursky
• 金额: $ 43.68万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 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/10475835
• 关键词: Address; Affect; Affinity; Affinity Chromatography; Aftercare; Alzheimer' 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; Crystallization; 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; Molecular; Molecular Conformation; Morbid Obesity; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcomes Research; Particle Size; Pathway interactions; Patients; Periodicity; Peripheral; Pilot Projects; Plasma; Population; Process; Progress Reports; Property; Proteins; Public Health; Publications; Receptor Cell; Research; Role; Serum amyloid A protein; Structure; Surface; Tail; Testing; Triglycerides; Very low density lipoprotein; Virus Diseases; Work; amyloid formation; bariatric surgery; base; 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

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 异常的脂蛋白代谢是肥胖的标志，影响> 40％的美国人。肥胖及其com- 包括2型糖尿病（T2D），心血管，淀粉样蛋白和严重病毒性疾病的植物是领先的 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 项目解决了肥胖症中脂蛋白功能中的关键未解决问题。高，低和非常低 - 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 血浆中直接脂质代谢。这个过程非常复杂，许多细节未知。我们的目前 重点是脂蛋白和蛋白质与硫酸乙酰肝素（HS）的相互作用，这可能会触发两种心脏 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 并改变肥胖症中的脂蛋白功能。我们强大的方法，它整合了各种各样的生物化学 ICAL，生物物理和计算工具，使我们能够假设将要测试的新假设 在三个互补的特定目标中。 AIM 1将确定肥胖症的脂蛋白功能如何变化 前后治疗。来自健康和病态肥胖受试者的脂蛋白将根据 将确定肝素结合亲和力及其生化和功能特性。我们的新假设 将在强大的试点研究的支持下进行测试：脂蛋白脂肪酶对循环的作用形成的小颗粒 lating VLDL提供了肥胖和读数的新型生物标志物。 AIM 2将定义生化 血清淀粉样蛋白A（SAA）的功能细节从肥胖症中从HDL转移到LDL。我们的试点研究表明 这种小蛋白质的转移会引起LDL的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，升高的SAA和动脉粥样硬化和II）的新机械联系 SAA在肥胖中的角色。 AIM 3将决定HS和肝素如何影响SAA的错误折叠 淀粉样蛋白A（AA）淀粉样变性，肥胖和慢性炎症的生命并发症。 SAA结合到 HS是AA淀粉样变性的治疗靶标，但缺乏分子细节。我们的试点研究表明：我） 与HS结合的SAA启动了淀粉样蛋白沉积的细胞外途径。 ii）HS结合的周期性阴离子阵列 淀粉样蛋白中的一堆基本残基并稳定淀粉样核。为了测试这些有趣的新想法，我们将 结合生化，生物物理，氢欧交换质谱和计算甲 晶体和原纤维中SAA原子结构的OD。结果：这项研究将确定新的机械 肥胖与动脉粥样硬化之间的联系；验证SAA作为脂质清道夫的假设至关重要的作用；阐明 它在淀粉样蛋白中的错误折叠途径；并帮助开发新的诊断工具和治疗肥胖和相关的治疗方法 疾病。这项研究的更广泛的影响是：i）帮助理解和调节因果关系 肥胖，T2D和严重的Covid-19疾病，以及II）发现HS-淀粉样蛋白间的分子基础 不仅在AA中，而且还会影响阿尔茨海默氏症和其他主要淀粉样蛋白疾病的行为。