Our lab discovered RTN-4B (called Nogo-B) as a protein highly abundant in endothelial cells (EC) and vascular smooth muscle (VSM) cells and mice deficient in Nogo-B have accelerated neointima after vascular injury, defective wound healing and impaired blood flow recovery post-ischemia. In exciting, preliminary data, we show that Nogo-B in the endothelium regulates the acute inflammatory response and neutrophil transmigration in vitro and in vivo. Mechanistically, the loss of Nogo suppresses ICAM-1 mediated signaling and the phosphorylation of VE cadherin in EC, which contributes to reduced inflammation in mice lacking Nogo-B. In a separate series of experiments examining the intracellular function of NgBR, we have discovered that in addition to binding Nogo-B, NgBR is critical for regulating intracellular cholesterol metabolism by stabilizing the Niemann Pick C2 protein (NPC2), raising the possibility that Nogo-B/NgBR signaling exerts a fundamental role in basic aspects of cholesterol homeostasis. In order to understand the integrated role of NgBR, we have generated conditional knockout mice and will examine its role in several experimental vascular paradigms that are impaired in Nogo-A/B KO mice. Thus, we hypothesize that Nogo-B and NgBR function as a novel endogenous regulatory system that coordinates the response to vascular injury or tissue ischemia and regulates endoplasmic reticulum (ER) functions such as cholesterol metabolism via stabilization of NPC2. In this proposal we will: 1. Define how Nogo-B regulates leukocyte transendothelial migration and vascular inflammation;2. Examine Nogo-B regulation of NgBR mediated stabilization of NPC2 and cellular cholesterol metabolism;and 3. Characterize conditional NgBR knockout mice. Overall, the central goal of this proposal is to broadly understand the functions of Nogo-B as a prototypical reticulon family member and to examine its functions as a regulator of vascular homeostasis.

Public Health Relevance

This research is relevant to public health since inflammation is a common manifestation of most cardiovascular diseases. Our research has discovered a new modulator of blood vessel function and remodeling during atherosclerosis or hypertension. Research supported by this grant may help identify new drugs that reduce heart disease and improve the quality of life of people suffering with cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL081190-07
Application #
8096670
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Gao, Yunling
Project Start
2005-08-01
Project End
2015-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
7
Fiscal Year
2011
Total Cost
$421,899
Indirect Cost
Name
Yale University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Grabi?ska, Kariona A; Park, Eon Joo; Sessa, William C (2016) cis-Prenyltransferase: New Insights into Protein Glycosylation, Rubber Synthesis, and Human Diseases. J Biol Chem 291:18582-90
Park, Eon Joo; Grabi?ska, Kariona A; Guan, Ziqiang et al. (2016) NgBR is essential for endothelial cell glycosylation and vascular development. EMBO Rep 17:167-77
Kraehling, Jan R; Hao, Zhengrong; Lee, Monica Y et al. (2016) Uncoupling Caveolae From Intracellular Signaling In Vivo. Circ Res 118:48-55
Marin, Ethan P; Jozsef, Levente; Di Lorenzo, Annarita et al. (2016) The Protein Acyl Transferase ZDHHC21 Modulates ?1 Adrenergic Receptor Function and Regulates Hemodynamics. Arterioscler Thromb Vasc Biol 36:370-9
Kraehling, Jan R; Sessa, William C (2015) Enhanced eNOS Activation as the Fountain of Youth for Vascular Disease: Is BPIFB4 What Ponce de León Was Looking For? Circ Res 117:309-10
Siragusa, Mauro; Fröhlich, Florian; Park, Eon Joo et al. (2015) Stromal cell-derived factor 2 is critical for Hsp90-dependent eNOS activation. Sci Signal 8:ra81
Landskroner-Eiger, Shira; Qiu, Cong; Perrotta, Paola et al. (2015) Endothelial miR-17?92 cluster negatively regulates arteriogenesis via miRNA-19 repression of WNT signaling. Proc Natl Acad Sci U S A 112:12812-7
Goodwin, Julie E; Zhang, Xinbo; Rotllan, Noemi et al. (2015) Endothelial glucocorticoid receptor suppresses atherogenesis--brief report. Arterioscler Thromb Vasc Biol 35:779-782
Lee, Monica Y; Luciano, Amelia K; Ackah, Eric et al. (2014) Endothelial Akt1 mediates angiogenesis by phosphorylating multiple angiogenic substrates. Proc Natl Acad Sci U S A 111:12865-70
Goodwin, Julie E; Feng, Yan; Velazquez, Heino et al. (2014) Loss of the endothelial glucocorticoid receptor prevents the therapeutic protection afforded by dexamethasone after LPS. PLoS One 9:e108126

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