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Transendothelial transport mediated modulations to the High Density Lipoprotein

跨内皮转运介导的高密度脂蛋白调节

基本信息

批准号：
10245152
负责人：
VASANTHY NARAYANASWAMI
金额：
$ 11.06万
依托单位：
CALIFORNIA STATE UNIVERSITY LONG BEACH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10245152
关键词：
ATP-Binding Cassette Transporters Address Amphipathic Alpha Helix Antiatherogenic Antioxidants Apolipoprotein A-I Apolipoproteins Arterial Fatty Streak Arterial Intimas Arylesterase Attention Biomedical Research Blood Vessels Cardiovascular Diseases Cardiovascular system Cellular biology Cholesterol Collaborations Communities Development Endothelial Cells Evaluation Exhibits Fluorescent Probes Funding Future Goals High Density Lipoprotein Cholesterol High Density Lipoproteins Impairment In Vitro Joints Knowledge Leadership Life Style Light Lipids Lipoproteins Literature Location Low Density Lipoprotein oxidation Mass Spectrum Analysis Mediating Mentors Mentorship Metabolism Modification Molecular Conformation Outcome Particle Size Patients Pharmacology Plasma Post-Translational Protein Processing Property Proteins Proteomics Publications Publishing Reporting Research Research Training Risk Role Structure Structure-Activity Relationship Students Testing Ursidae Family antioxidant enzyme apolipoprotein E-3 atheroprotective base biomarker identification cardiovascular disorder risk cardiovascular risk factor conformational alteration flexibility gene therapy improved insight lipidomics macrophage monolayer particle prevent reconstitution response skills symposium training opportunity transcytosis

项目摘要

Title: Transendothelial transport mediated modulations to the High Density Lipoprotein Summary Despite the vast amount of literature that indicates low plasma levels of HDL-cholesterol (HDL-C) is a risk factor for cardiovascular disease (CVD), the last decade has seen a paradigm shift in the concept that it may not be HDL-C levels per se but the functionality of HDL that is a determining factor in CVD. The shift in focus is in light of several studies that show that neither pharmacological nor genetic intervention to increase HDL-C levels, lower the risk for CVD. Thus, there is a pressing need to fill the gap in knowledge regarding the role of HDL in CVD from a mechanistic perspective and understand structure-function relationships in HDL. In the current proposal, we hypothesize that apolipoprotein (apo) AI and apoE3, two critical apos on HDL, undergo structural alterations and post translational modifications (PTM) and that HDL undergoes particle modulation as a consequence of transendothelial transport from plasma to the arterial intima with significant functional penalties. We will test this hypothesis by interrogating structure-function changes to the HDL with two specific aims: (1) Identify structural and proteomic alterations to the HDL associated with transendothelial transport across aortic endothelial cells, and, (2) Determine changes in HDL function following transendothelial transport. We will carry out spectroscopic analysis of reconstituted HDL (rHDL) bearing spatially sensitive fluorescent probes at flexible locations on apoAI or apoE3 to obtain insight into conformational alterations following transcytosis. Based on previous findings about oxidatively modified apoAI in atherosclerotic plaques, we postulate that the apos are susceptible to oxidative modification during transcytosis. To address this, we will determine PTM in transcytosed HDL, specifically on apoAI, apoE3 and selected proteins involved in lipoprotein metabolism by mass spectrometry. We will also perform lipoproteomic analysis to identify changes to the protein and lipid composition of transcytosed HDL. In an independent but complementary approach, we will examine changes in two major functional effects of transcytosed HDL: its ability to promote cholesterol efflux from macrophages, and, its antioxidant activity. Completion of these studies will significantly advance our understanding of the relationship between structure/composition and the atheroprotective effect of HDL at the vascular wall. The expected outcome of the proposed studies is to have a deeper understanding of modulations in HDL that render it dysfunctional. Establishing this relationship will aid in development of HDL- based therapies and identification of biomarkers of CVD risk. The research enhancement objectives of the PI are to: (i) develop expertise in HDL and endothelial cell biology, (ii) increase competitiveness to apply for major external funding by publishing research findings, (iii) strengthen existing and develop new collaborations, submit joint publications and lay the groundwork for developing proposals, and, (iv) establish mentoring, networking, and leadership skills, and offer research training opportunities and mentorship for students from diverse backgrounds in biomedical research.

题目：经内皮转运介导的高密度脂蛋白调节

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Apolipoprotein E LDL receptor-binding domain-containing high-density lipoprotein: a nanovehicle to transport curcumin, an antioxidant and anti-amyloid bioflavonoid.

DOI：
10.1016/j.bbamem.2010.09.007
发表时间：
2011-01
期刊：
Biochimica et biophysica acta
影响因子：
0
作者：
Khumsupan P;Ramirez R;Khumsupan D;Narayanaswami V
通讯作者：
Narayanaswami V

Targeted intracellular delivery of resveratrol to glioblastoma cells using apolipoprotein E-containing reconstituted HDL as a nanovehicle.

DOI：
10.1371/journal.pone.0135130
发表时间：
2015
期刊：
PloS one
影响因子：
3.7
作者：
Kim SH;Adhikari BB;Cruz S;Schramm MP;Vinson JA;Narayanaswami V
通讯作者：
Narayanaswami V

Biochemical and biophysical characterization of recombinant rat apolipoprotein E: similarities to human apolipoprotein E3.

重组大鼠载脂蛋白 E 的生化和生物物理特征：与人载脂蛋白 E3 的相似性。

DOI：
10.1016/j.abb.2012.10.007
发表时间：
2013
期刊：
Archives of biochemistry and biophysics
影响因子：
3.9
作者：
Tran,TuyenN;Kim,SeaH;Gallo,Carlos;Amaya,Max;Kyees,Jessica;Narayanaswami,Vasanthy
通讯作者：
Narayanaswami,Vasanthy

Ordered opening of LDL receptor binding domain of human apolipoprotein E3 revealed by hydrogen/deuterium exchange mass spectrometry and fluorescence spectroscopy.

氢/氘交换质谱和荧光光谱显示人载脂蛋白 E3 的 LDL 受体结合域有序开放。

DOI：
10.1016/j.bbapap.2018.08.005
发表时间：
2018
期刊：
Biochimica et biophysica acta. Proteins and proteomics
影响因子：
0
作者：
Yang,Liping;Hernandez,RoyV;Tran,TuyenN;Nirudodhi,Sasidhar;Beck,WendyHJ;Maier,ClaudiaS;Narayanaswami,Vasanthy
通讯作者：
Narayanaswami,Vasanthy

Apolipoprotein E3-mediated cellular uptake of reconstituted high-density lipoprotein bearing core 3, 10, or 17 nm hydrophobic gold nanoparticles.