Jianxin Sun, PhD

Center for
Translational Medicine
1025 Walnut Street, Suite 408
Philadelphia, PA 19107

(215) 503-9425
(215) 503-5731 fax

Medical School
Second Military Medical University, China, 1987

Fellowship
Harvard Medical School

Degree
Ph.D. Shanghai Institute of Biochemistry and Cell Biology, CAS, 1998

University Appointment
Associate Professor of Medicine

Research and Clinical Interests
Currently our laboratory has the following two major research interests:

1) Molecular mechanisms of vascular inflammation. Vascular inflammation plays an important role in the development and progression of cardiovascular diseases such as atherosclerosis and diabetic vascular complications. Recently, we identified two molecules, namely Nur77 and TNF-α inducible protein1 (TNFAIP1), in vascular endothelial cells that are rapidly induced in response to inflammatory stimuli, such as Tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and lipopolysaccharide (LPS). Preliminary results suggest that nuclear orphan receptor Nur77 exerts potent anti-inflammatory effects in human endothelial cells via an up-regulation of IkBα expression, thus constitutes a negative feedback mechanism in inhibiting vascular inflammation. However, the role of endogenous Nur77 in IkB expression and NF-k B activation in endothelial cells (ECs) remains to be determined. In addition, the transcriptional targets of Nur77 are largely unknown and will be further investigated by genomics and proteomics in ECs and macrophages. Furthermore, the effect of Nur77 genetic deletion on EC activation, vascular inflammation will be assessed in murine models of atherosclerosis. TNFAIP1 was first identified as a TNF-α inducible protein in ECs, the function of TNFAIP1 in vascular inflammation, however, remains largely unknown. Our preliminary results suggest that TNFAIP1 can markedly potentiate the TNF-α and LPS-induced inflammatory responses in endothelial cells. The underlying mechanism turned out to be related to the TNFAIP1 mediated TNF-receptor associated factors (TRAFs) ubiquitination and subsequent NF-kB activation. The precise role of TNFAIP1 in the vascular inflammation will be further dissected by using a combination of genetic, biochemical, genomic and proteomic approaches.

2) Regulation of endothelia nitric oxide synthase expression and activity. Endothelium-derived nitric oxide (NO) is an important regulator of vascular function. NO is produced by endothelial NO synthase (eNOS) whose expression is modulated, in part, at posttranscriptional levels. To elucidate the molecular basis of TNF-α-mediated posttranscriptional control via mRNA stabilization, eNOS 3' untranslated region (3'-UTR) binding proteins were purified by RNA affinity chromatography from a cytosolic fraction of TNF-α stimulated human umbilical vein endothelial cells (HUVECs) and identified by proteomic methods in the laboratory. We, for the first time, found that translation elongation factor 1-alpha 1 (eEF1A1) is a novel trans-acting factor that binds to eNOS mRNA in response to TNF-α stimulation. The interaction of eEF1A1 with eNOS 3'-UTR was demonstrated by RNA gel mobility shift and UV cross-linking assays. The functional significance of eEF1A1 in the regulation of eNOS mRNA stability was confirmed by eEF1A1 gene over-expression and siRNA mediated gene knockdown in endothelial cells. We are generating dominant negative eEF1A1 and cell permeable peptides derived from eNOS mRNA binding motif in eEF1A1 to investigate the in vivo functional significance in the regulation of vascular homeostasis. In addition, we will continue to identify the 3'-UTR ribonucleoprotein complexes by mass spectrometry and study their roles in the regulation of eNOS mRNA stability and their involvements in the endothelial dysfunction associated with many cardiovascular diseases.

Publications

Most Recent Peer-reviewed Publications

1. FHL-2 suppresses VEGF-induced phosphatidylinositol 3-kinase/Akt activation via interaction with sphingosine kinase-1
2. The orphan nuclear receptor Nur77 suppresses endothelial cell activation through induction of IκBα expression
3. Phosphorylation of cardiac troponin I by mammalian sterile 20-like kinase 1
4. Tumor necrosis factor-α downregulates endothelial nitric oxide synthase mRNA stability via translation elongation factor 1-α 1
5. ROCK1 mediates leukocyte recruitment and neointima formation following vascular injury
6. Activation of sphingosine kinase-1 mediates induction of endothelial cell proliferation and angiogenesis by epoxyeicosatrienoic acids
7. Down-regulation of mammalian sterile 20-like kinase 1 by heat shock protein 70 mediates cisplatin resistance in prostate cancer cells
8. Activation of sphingosine kinase-1 mediates inhibition of vascular smooth muscle cell apoptosis by hyperglycemia
9. Transcriptome analysis of the salivary glands of Dermacentor andersoni Stiles (Acari: Ixodidae)
10. FHL2/SLIM3 decreases cardiomyocyte survival by inhibitory interaction with sphingosine kinase-1
11. Induction of angiogenesis by heat shock protein 90 mediated by protein kinase Akt and endothelial nitric oxide synthase
12. 11,12-Epoxyeicosatrienoic acid (11,12-EET): Structural determinants for inhibition of TNF-α-induced VCAM-1 expression
13. Tissue- and Stage-specific Expression of Two Lipophorin Receptor Variants with Seven and Eight Ligand-binding Repeats in the Adult Mosquito
14. Activation of the phosphatidylinositol 3-kinase/protein kinase Akt pathway mediates nitric oxide-induced endothelial cell migration and angiogenesis
15. Functional interaction of endothelial nitric oxide synthase with a voltage-dependent anion channel
16. 1α,25-dihydroxyvitamin D3 induces vascular smooth muscle cell migration via activation of phosphatidylinositol 3-kinase
17. Rho-kinase mediates hypoxia-induced downregulation of endothelial nitric oxide synthase
18. Inhibition of vascular smooth muscle cell migration by cytochrome P450 epoxygenase-derived eicosanoids
19. Molecular characterization of the VLDL receptor homolog mediating binding of lipophorin in oocyte of the mosquito Aedes aegypti
20. Regulation of Myogenic Terminal Differentiation by the Hairy-related Transcription Factor CHF2

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