A5037865809- Alzheimer's disease research and treatments
- Neurogenesis and neuroplasticity mechanisms
- Protease and Inhibitor Mechanisms
- Lipoproteins and Cardiovascular Health
- Cholesterol and Lipid Metabolism
- Cancer, Lipids, and Metabolism
- Neuroinflammation and Neurodegeneration Mechanisms
- Cellular transport and secretion
- Neuroscience and Neuropharmacology Research
- Axon Guidance and Neuronal Signaling
- Signaling Pathways in Disease
- Nuclear Receptors and Signaling
- Cell Adhesion Molecules Research
- Caveolin-1 and cellular processes
- Amyotrophic Lateral Sclerosis Research
- Ubiquitin and proteasome pathways
- Atherosclerosis and Cardiovascular Diseases
- RNA Research and Splicing
- Wnt/β-catenin signaling in development and cancer
- Diabetes, Cardiovascular Risks, and Lipoproteins
- Mitochondrial Function and Pathology
- Blood Coagulation and Thrombosis Mechanisms
- Endoplasmic Reticulum Stress and Disease
- Peroxisome Proliferator-Activated Receptors
- Genetics and Neurodevelopmental Disorders
The University of Texas Southwestern Medical Center
2016-2025
Southwestern Medical Center
2012-2024
Vivantes Klinikum
2024
Korea National Institute of Health
2024
Hudson Institute
2024
John Wiley & Sons (United States)
2024
The University of Texas at Dallas
2019-2022
University of Freiburg
2005-2021
Society for Neuroscience
2011-2021
Nanotherapeutics (United States)
2013-2021
Background: Mutations in the tyrosine kinase (TK) domain of epidermal growth factor receptor (EGFR) gene lung cancers are associated with increased sensitivity these to drugs that inhibit EGFR activity. However, role such mutations pathogenesis is unclear. Methods: We sequenced exons 18–21 TK from genomic DNA isolated 617 non-small-cell (NSCLCs) and 524 normal tissue samples same patients 36 neuroendocrine tumors collected Japan, Taiwan, United States, Australia 243 other epithelial cancers....
A defect in Klotho gene expression mice accelerates the degeneration of multiple age-sensitive traits. Here, we show that overexpression extends life span. protein functions as a circulating hormone binds to cell-surface receptor and represses intracellular signals insulin insulin-like growth factor 1 (IGF1), an evolutionarily conserved mechanism for extending Alleviation aging-like phenotypes Klotho-deficient was observed by perturbing IGF1 signaling, suggesting Klotho-mediated inhibition...
We employed homologous recombination in embryonic stem cells to produce mice lacking functional LDL receptor genes. Homozygous male and female receptors (LDLR-/- mice) were viable fertile. Total plasma cholesterol levels twofold higher than those of wild-type litter-mates, owing a seven- ninefold increase intermediate density lipoproteins (IDL) without significant change HDL. Plasma triglyceride normal. The half-lives for intravenously administered 125I-VLDL 125I-LDL prolonged by 30-fold...
Plasma high density lipoprotein (HDL), which protects against atherosclerosis, is thought to remove cholesterol from peripheral tissues and deliver cholesteryl esters via a selective uptake pathway the liver (reverse transport) steroidogenic (e.g., adrenal gland for storage hormone synthesis). Despite its physiologic pathophysiologic importance, cellular metabolism of HDL has not been well defined. The class B, type I scavenger receptor (SR-BI) proposed play an important role in because ( i...
Multiligand receptorsLigand families and subgroups their binding sites on LRP recognizes at least 30 different ligands (Table 1) that represent several of proteins.These include lipoproteins, proteinases, proteinaseinhibitor complexes, ECM proteins, bacterial toxins, viruses, various intracellular proteins.
Mice that are homozygous for a targeted disruption of the LDL receptor gene (LDLR-/- mice) were fed diet contained 1.25% cholesterol, 7.5% cocoa butter, casein, and 0.5% cholic acid. The total plasma cholesterol rose from 246 to > 1,500 mg/dl, associated with marked increase in VLDL, intermediate density lipoproteins (IDL), decrease HDL cholesterol. In wild type littermates same diet, remained < 160 mg/dl. After 7 mo, LDLR-/- mice developed massive xanthomatous infiltration skin subcutaneous...
Two apolipoprotein E (apoE) receptors, the very low density lipoprotein (VLDL) receptor and apoE 2 (apoER2), are also receptors for Reelin, a signaling protein that regulates neuronal migration during brain development. In adult brain, Reelin is expressed by GABA-ergic interneurons, suggesting potential function as modulator of neurotransmission. ApoE have been indirectly implicated in memory neurodegenerative disorders because their ligand, apoE, genetically associated with Alzheimer...
Low density lipoprotein receptor-related protein (LRP) is a recently described cell-surface of 4544 amino acids that contains reiterated sequences found in the 839-amino acid receptor for low (LDL). In current studies, we purified LRP from rat liver, prepared polyclonal antibodies recognize extracellular domain, and demonstrated an immunoreactive approximately 600 kDa human fibroblasts. The function this was studied mutant fibroblasts do not produce LDL receptors. cells were incubated with...
A 39-kDa protein of unknown function has previously been reported to copurify with the low density lipoprotein receptor-related (LRP)/alpha 2-macroglobulin receptor. In this study we demonstrate that a recombinant fusion can reversibly bind 515-kDa subunit LRP/alpha This interaction inhibits binding and uptake receptor's two known ligands: 1) beta-migrating very lipoproteins activated by enrichment apoprotein E 2) alpha incubation plasma proteases or methylamine. potential in vivo role is...
Vascular smooth muscle cell (SMC) proliferation and migration are important events in the development of atherosclerosis. The low-density lipoprotein receptor-related protein (LRP1) mediates suppression SMC induced by platelet-derived growth factor (PDGF). Here we show that LRP1 forms a complex with PDGF receptor (PDGFR). Inactivation vascular SMCs mice causes PDGFR overexpression abnormal activation signaling, resulting disruption elastic layer, proliferation, aneurysm formation, marked...
Apolipoprotein E, α<sub>2</sub>-macroglobulin, and amyloid precursor protein (APP) are involved in the development of Alzheimer's disease. All three proteins ligands for low density lipoprotein (LDL) receptor-related (LRP), an abundant neuronal surface receptor that has also been genetically linked to The cytoplasmic tails LRP other members LDL gene family contain NPxY motifs required endocytosis. To investigate whether these receptors may have functions go beyond ligand internalization,...
The members of the low density lipoprotein (LDL) receptor gene family bind a broad spectrum extracellular ligands. Traditionally, they had been regarded as mere cargo receptors that promote endocytosis and lysosomal delivery these However, recent genetic experiments in mice have revealed critical functions for two LDL members, very apoE receptor-2, transmission signals activation intracellular tyrosine kinases. This process regulates neuronal migration is crucial brain development. Signaling...
The low density lipoprotein receptor-related protein (LRP) from rat liver membranes binds apoprotein E (apoE)-enriched rabbit beta-migrating very lipoproteins (beta-VLDL) in a ligand blotting assay on nitrocellulose membranes. Binding was markedly activated when the beta-VLDL preincubated with recombinant human apoE-3, native apoE-3 or E-4, apoE. Human apoE-2, which poorly (1-2% of apo E-3 binding) to receptors, approximately 40% as effective apoE-4 binding LRP. Stimulation apoE-dependent...
The synthesis of cholesterol and its uptake from plasma LDL are regulated by two membrane-bound transcription factors, designated sterol regulatory element binding protein-1 -2 (SREBP-1 SREBP-2). Here, we used the technique homologous recombination to generate mice with disruptions in gene encoding isoforms SREBP-1, termed SREBP-1a SREBP-1c. Heterozygous gene-disrupted were phenotypically normal, but 50- 85% homozygous (-/-) died utero at embryonic day 11. surviving -/- appeared normal birth...
TAR DNA-binding protein 43 (TDP-43) is associated with a spectrum of neurodegenerative diseases. Although TDP-43 resembles heterogeneous nuclear ribonucleoproteins, its RNA targets and physiological partners remain unknown. Here we identify from cortical neurons by immunoprecipitation followed deep sequencing (RIP-seq). The canonical binding site (TG)n 55.1-fold enriched, moreover, variant adenine in the middle, (TG)nTA(TG)m, highly abundant among reads our RIP-seq library. can be divided...
Apolipoprotein E (apoE) is hypothesized to mediate lipoprotein clearance by binding two receptors: (i) the low density receptor (LDLR) and (ii) a chylomicron remnant receptor. To test this hypothesis, we have compared plasma lipoproteins in mice that are homozygous for targeted disruptions of genes apoE [apoE(-/-)], LDLR [LDLR(-/-)], both molecules [poE(-/-); LDLR(-/-)]. On normal chow diet, apoE(-/-) had higher mean cholesterol levels than LDLR(-/-) (579 vs. 268 mg/dl). Cholesterol...