A5078980138- Diabetes, Cardiovascular Risks, and Lipoproteins
- Metabolomics and Mass Spectrometry Studies
- Lipid metabolism and disorders
- Metabolism and Genetic Disorders
- Cancer, Lipids, and Metabolism
- Lipoproteins and Cardiovascular Health
- Immune Cell Function and Interaction
- Diet and metabolism studies
- Cholesterol and Lipid Metabolism
- Folate and B Vitamins Research
- Advanced Proteomics Techniques and Applications
- Immunotherapy and Immune Responses
- Peroxisome Proliferator-Activated Receptors
- Immune Response and Inflammation
- Diet, Metabolism, and Disease
- T-cell and B-cell Immunology
- Metabolism, Diabetes, and Cancer
- Immunodeficiency and Autoimmune Disorders
- Inflammasome and immune disorders
- Diabetes Treatment and Management
- Mitochondrial Function and Pathology
- RNA Interference and Gene Delivery
- Cancer, Hypoxia, and Metabolism
- Cardiac Valve Diseases and Treatments
- Mass Spectrometry Techniques and Applications
Harvard University
2015-2024
National Heart Lung and Blood Institute
2013-2015
National Institutes of Health
2013-2015
Significance IL-21 is a type I cytokine important for immune cell differentiation and function. We found that transcription factors STAT1 STAT3 play partially opposing roles in function CD4 + T cells. Both control IL-21–mediated gene regulation, with some genes, including Ifng , Tbx21 Il21 reciprocally regulated by these STATs. IFN-γ production was also differentially STATs vitro during T-cell vivo chronic lymphocytic choriomeningitis infection. Importantly, IL-21–induced IFNG TBX21...
Objective— HDL (high-density lipoprotein) in plasma is a heterogeneous group of lipoproteins typically containing apo AI as the principal protein. Most HDLs contain additional proteins from palate nearly 100 HDL-associated polypeptides. We hypothesized that some these define distinct and stable subspecies with unique proteomes drive function associations disease. Approach Results— produced 17 pools 80 normolipidemic human participants (32 men, 48 women; aged 21–66 years). Using...
Calcific aortic valve disease (CAVD) occurs when subpopulations of cells undergo specific differentiation pathways, promoting tissue fibrosis and calcification. Lipoprotein particles carry oxidized lipids that promote valvular disease, but low-density lipoprotein–lowering therapies have failed in clinical trials, there are currently no pharmacological interventions available for this disease. Apolipoproteins known promoters atherosclerosis, whether they possess pathogenic properties CAVD is...
HDLs are a family of heterogeneous particles that vary in size, composition, and function. The structure most is maintained by two scaffold proteins, apoA-I apoA-II, but up to 95 other "accessory" proteins have been found associated with the particles. Recent evidence suggests these accessory distributed across various subspecies drive specific biological functions. Unfortunately, our understanding molecular composition such limited. To begin address this issue, we separated human plasma HDL...
Endogenous labeling with stable isotopes is used to study the metabolism of proteins in vivo. However, traditional detection methods such as GC/MS cannot measure tracer enrichment multiple simultaneously, and reaction monitoring MS precisely low slowly turning-over HDL. We exploited versatility high-resolution/accurate mass (HR/AM) quadrupole Orbitrap for proteomic analysis five HDL sizes. identified 58 that were shared among three humans organized into subproteomes according size. For seven...
Abstract The canonical pathway for IL-1β production requires TLR-mediated NF-κB-dependent Il1b gene induction, followed by caspase-containing inflammasome-mediated processing of pro-IL-1β. Here we show that IL-21 unexpectedly induces in conventional dendritic cells (cDCs) via a STAT3-dependent but NF-κB-independent pathway. does not induce expression CD4 + T cells, with differential histone marks present these versus cDCs. IL-21-induced cDCs require caspase-1 or caspase-8 depends on...
Objective: Clinical evidence has linked low HDL (high-density lipoprotein) cholesterol levels with high cardiovascular disease risk; however, its significance as a therapeutic target remains unestablished. We hypothesize that HDLs functional heterogeneity is comprised of metabolically distinct proteins, each on sizes and are affected by diet. Approach Results: Twelve participants were placed 2 healthful diets in monounsaturated fat or carbohydrate. After 4 weeks diet, completed metabolic...
Recent in vivo tracer studies demonstrated that targeted mass spectrometry (MS) on the Q Exactive Orbitrap could determine metabolism of HDL proteins 100s-fold less abundant than apolipoprotein A1 (APOA1). In this study, we demonstrate Lumos can measure whose abundances are 1000s-fold APOA1, specifically lipid transfer phospholipid protein (PLTP), cholesterol ester (CETP), and lecithin-cholesterol acyl transferase (LCAT). Relative to Exactive, improved detection by reducing enrichment...
Apolipoprotein A4's (APOA4's) functions on HDL in humans are not well understood. A unique feature of APOA4 is that it an intestinal apolipoprotein secreted and chylomicrons. The goal this study was to gain a better understanding the origin function by studying its metabolism across 6 sizes. Twelve participants completed metabolic tracer study. isolated APOA1 immunopurification separated size. Tracer enrichments for were determined targeted mass spectrometry, rates derived compartmental...
We developed an automated quantification workflow for PRM‐enabled detection of D3‐Leu labeled apoA‐I in high‐density lipoprotein (HDL) isolated from humans. Subjects received a bolus injection and blood was drawn at eight time points over three days. HDL separated into six size fractions subsequent proteolysis PRM analysis the signal ∼0.03 to 0.6% enrichment. implemented intensity‐based approach that takes advantage high‐resolution/accurate mass scans identify 2HM3 ion non‐specific peaks....
Humans spend much of the day in postprandial state. However, most research and clinical guidelines on plasma lipids pertain to blood drawn after a 12-hour fast. We aimed study metabolic differences apoB lipoproteins between fasting states.
Introduction: When dietary carbohydrate replaces fat, HDL cholesterol (HDL-C) and the primary protein apolipoprotein A1 (apoA1) decrease. The proportion in plasma of large HDL2 decreases while small HDL3 increases. These findings suggest that diet affects metabolically important attributes produce size changes. We studied humans effect unsaturated fat on proteome metabolism 9 proteins across 5 sizes. Methods Results: Twelve participants were placed a healthy, controlled high (HF) or (HC)...
Introduction: The composition of specific apolipoproteins may determine HDL functions. We present novel mass spectrometry (MS)-based methods that capture the absolute quantities and kinetics 7 in 5 size fractions. Methods Results: Three participants were recruited, infused with a bolus D3-Leu tracer, blood was collected for 70 hrs. ApoA-I-containing prepared by immunoaffinity purification, separated into fractions, preβ, α3, α2, α1, α0 ND-PAGE, in-gel trypsinized MS. monitored proteins...
Introduction: Studying the kinetics of several HDL apolipoproteins together may help elucidate their function in metabolism. We present multicompartmental analysis describing metabolism across 5 size fractions. Methods and Results: Three participants were infused with a bolus D3-Leu tracer, blood was collected for 70 hrs. ApoA-I-HDL prepared by immunoaffinity purification, separated into fractions, preβ, α3, α2, α1, α0, ND-PAGE, in-gel trypsinized mass spectrometry. monitored 7 proteins that...
High-density lipoproteins (HDL) play a critical role in lipid transport and the maintenance of vascular homeostasis. HDL consists heterogeneous population particles that vary size, composition, functionality. is proteomically diverse; it can host at least 95 different proteins structure-function studies suggest specific protein complements on surface are responsible for broad spectrum function. The goal this study was to isolate fully characterize subspecies based their complement particle...
Introduction: When dietary carbohydrate replaces fat, HDL-C and apoA1 decrease. The proportion in plasma of large HDL2 decreases while small HDL3 increases. These findings suggest that diet affects metabolically important attributes HDL produce the size changes. We studied humans effect unsaturated fat on proteome metabolism 9 proteins across 6 sizes. Methods Results: Twelve participants were placed a controlled high (HF) or (HC) randomized crossover design. At end each 4-week period,...