The goal of this resource is to synthesize a wide range of variants of bioactive sphingosine 1-phosphate (81P) and glycosphingolipids that will be made available for collaborators with NHLBI and other investigators whose studies are pertinent to lung and vascular biology. The compounds to be prepared include chiral phosphonate and vinylphosphonate analogs of FTY720 and C-glycosides ofthe immunostimulatory glycolipid alpha-galactosylceramide. FTY720 is a structural analog of sphingosine that affects the activities of many enzymes in its unphosphorylated form, and is the first agent in a new class of small molecule SIP receptor agonists that alters lymphocyte traffic after it is phosphorylated by sphingosine kinase-2. The glycosphingolipicj alpha-galactosylceramide (alpha-GalCer, also known as KRN7000) is a synthetic analog of the marine natural product agelasphin that activates both human and mouse invariant natural killer T cells to produce immunoregulatory cytokines. Phosphonates and C-galactosides are metabolically stabilized derivatives of phosphate- and sugar-linked compounds, respectively. This proposal describes three projects related to pulmonary medicine that will be facilitated by the availability of unique analogs of the potent lipid mediators FTY720 and alpha-GalCer.
The specific aims are:
AIM 1. Inhibit SIP production and signaling in human pulmonary arterial smooth muscle cells by using analogs of (S)-FTY720-vinylphosphonate (a lead compound identified in previous studies supported by this grant as an inhibitor of sphingosine kinase).
AIM 2. Analyze the role of human plasma gelsolin in mediating the extracellular bioactivity of SIP and FTY720- phosphate, which act through the G protein-coupled receptors, in lung endothelial and lung epithelial cells.
AIM 3. Use alpha-C-GalCer analogs as adjuvants forthe live attenuated Bacillus Calmette-Guerin (BCG) vaccine.
Specific aims 1 and 2 will further our understanding ofthe physiological roles ofthe sphingosine kinase and the SIP signaling system in pathophysiology.
Specific aim 3 is anticipated to provide new insights into methods for developing vaccines with improved efficacy leading to control of tuberculosis.
This project will develop new chemical compounds that have the ability to alter cellular responses by acting on specific targets, leading to therapeutic treatments of human diseases and inflammatory disorders. The uses of the compounds include developing new approaches for prevention of pulmonary arterial hypertension, lung inflammation, and pulmonary infection from Mycobacterium tuberculosis.
|Venkataswamy, Manjunatha M; Ng, Tony W; Kharkwal, Shalu S et al. (2014) Improving Mycobacterium bovis bacillus Calmette-Guèrin as a vaccine delivery vector for viral antigens by incorporation of glycolipid activators of NKT cells. PLoS One 9:e108383|
|Liu, Zheng; Thacker, Seth G; Fernandez-Castillejo, Sara et al. (2014) Synthesis of cholesterol analogues bearing BODIPY fluorophores by Suzuki or Liebeskind-Srogl cross-coupling and evaluation of their potential for visualization of cholesterol pools. Chembiochem 15:2087-96|
|Neuvonen, Maarit; Manna, Moutusi; Mokkila, Sini et al. (2014) Enzymatic oxidation of cholesterol: properties and functional effects of cholestenone in cell membranes. PLoS One 9:e103743|
|Ohotski, Jan; Rosen, Hugh; Bittman, Robert et al. (2014) Sphingosine kinase 2 prevents the nuclear translocation of sphingosine 1-phosphate receptor-2 and tyrosine 416 phosphorylated c-Src and increases estrogen receptor negative MDA-MB-231 breast cancer cell growth: The role of sphingosine 1-phosphate receptor Cell Signal 26:1040-7|
|Ouro, Alberto; Arana, Lide; Gangoiti, Patricia et al. (2013) Ceramide 1-phosphate stimulates glucose uptake in macrophages. Cell Signal 25:786-95|
|Baek, Dong Jae; MacRitchie, Neil; Pyne, Nigel J et al. (2013) Synthesis of selective inhibitors of sphingosine kinase 1. Chem Commun (Camb) 49:2136-8|
|Carter Ramirez, Daniel M; Kim, Young Ah; Bittman, Robert et al. (2013) Lipid Phase Separation and Protein-Ganglioside Clustering in Supported Bilayers Are Induced by Photorelease of Ceramide. Soft Matter 9:4890-4899|
|Neviani, Paolo; Harb, Jason G; Oaks, Joshua J et al. (2013) PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells. J Clin Invest 123:4144-57|
|Liu, Zheng; MacRitchie, Neil; Pyne, Susan et al. (2013) Synthesis of (S)-FTY720 vinylphosphonate analogues and evaluation of their potential as sphingosine kinase 1 inhibitors and activators. Bioorg Med Chem 21:2503-10|
|Watson, David G; Tonelli, Francesca; Alossaimi, Manal et al. (2013) The roles of sphingosine kinases 1 and 2 in regulating the Warburg effect in prostate cancer cells. Cell Signal 25:1011-7|
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