The purpose of this application is to investigate novel functions of the low density lipoprotein (LDL) receptor gene family that go beyond its recognized role in the endocytosis of ligands and the control of triglyceride and cholesterol homeostasis. We will primarily address the cellular metabolism of two members of this evolutionarily highly conserved gene family, the very low density lipoprotein (VLDL) receptor and the LR8B, also known as apolipoprotein receptor-2. Recent findings that extracellular ligand interactions with these receptors may transmit signals to certain cell types and induce them to migrate through the surrounding tissue, a process of particular importance to the emerging roles of these genes in atherosclerosis and Alzheimer disease. Gene targeting was used to investigate the physiological functions of these genes in the mouse. The results of these preliminary experiments support the hypothesis that extracellular signals, transmitted by the VLDL receptor and LR8B, provide migratory cues to neurons during the formation of the brain. This signaling likely involves cytosolic adaptor proteins and non-receptor tyrosine kinases. To dissect and fully characterize the underlying pathway, mutations will be introduced into the cytoplasmic tails of both receptors that prevent them from interacting with the adaptor proteins, but will not affect their ability to undergo endocytosis. This will allow us to determine, whether a block of a signaling pathway or block of endocytosis of a specific ligand are responsible for the neuronal migration defect in VLDL receptor and LR8B deficient cells. We will extend these studies to search for novel adaptor proteins that interact with the cytoplasmic tails of LDL receptor gene family members in other tissues, in particular the liver and the vascular wall. There these interactions might modulate the ability of the receptors to remove lipoproteins from the circulation or affect the mechanisms that are the focus of this proposal are likely to have significant clinical implications and may provide new targets for drug design in the treatment of degenerative diseases of the brain and vascular wall.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063762-03
Application #
6499022
Study Section
Metabolism Study Section (MET)
Program Officer
Wassef, Momtaz K
Project Start
2000-02-01
Project End
2005-01-31
Budget Start
2002-02-01
Budget End
2003-01-31
Support Year
3
Fiscal Year
2002
Total Cost
$276,309
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Genetics
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
Abou-Jaoude, Antoine; Badiqué, Lise; Mlih, Mohamed et al. (2018) Loss of the adaptor protein ShcA in endothelial cells protects against monocyte macrophage adhesion, LDL-oxydation, and atherosclerotic lesion formation. Sci Rep 8:4501
Sacharidou, Anastasia; Chambliss, Ken L; Ulrich, Victoria et al. (2018) Antiphospholipid antibodies induce thrombosis by PP2A activation via apoER2-Dab2-SHC1 complex formation in endothelium. Blood 131:2097-2110
Lane-Donovan, Courtney; Herz, Joachim (2017) The ApoE receptors Vldlr and Apoer2 in central nervous system function and disease. J Lipid Res 58:1036-1043
van de Sluis, Bart; Wijers, Melinde; Herz, Joachim (2017) News on the molecular regulation and function of hepatic low-density lipoprotein receptor and LDLR-related protein 1. Curr Opin Lipidol 28:241-247
Wasser, Catherine R; Herz, Joachim (2017) Reelin: Neurodevelopmental Architect and Homeostatic Regulator of Excitatory Synapses. J Biol Chem 292:1330-1338
Ding, Yinyuan; Huang, Linzhang; Xian, Xunde et al. (2016) Loss of Reelin protects against atherosclerosis by reducing leukocyte-endothelial cell adhesion and lesion macrophage accumulation. Sci Signal 9:ra29
El Asmar, Zeina; Terrand, Jérome; Jenty, Marion et al. (2016) Convergent Signaling Pathways Controlled by LRP1 (Receptor-related Protein 1) Cytoplasmic and Extracellular Domains Limit Cellular Cholesterol Accumulation. J Biol Chem 291:5116-27
Ding, Yinyuan; Xian, Xunde; Holland, William L et al. (2016) Low-Density Lipoprotein Receptor-Related Protein-1 Protects Against Hepatic Insulin Resistance and Hepatic Steatosis. EBioMedicine 7:135-45
Eldridge, Suzanne; Nalesso, Giovanna; Ismail, Habib et al. (2016) Agrin mediates chondrocyte homeostasis and requires both LRP4 and ?-dystroglycan to enhance cartilage formation in vitro and in vivo. Ann Rheum Dis 75:1228-35
Pohlkamp, Theresa; Durakoglugil, Murat; Lane-Donovan, Courtney et al. (2015) Lrp4 domains differentially regulate limb/brain development and synaptic plasticity. PLoS One 10:e0116701

Showing the most recent 10 out of 82 publications