Understanding and manipulating complex protein-protein interactions required for physiological signaling during angiogenesis and vasculogenesis is an important step in developing prevention and treatment for hemorrhagic stroke. Disruption of these interactions or dysregulation of signaling proteins can result in defective vascular formation and subsequent disease. Cerebral cavernous malformation (CCM) is an example of a vascular anomaly in the brain caused by disruptions of signaling molecules that occurs naturally in 0.1 to 0.5% of the population. Genetic mutations at three loci are responsible for the inherited development of CCM. They encode three CCM proteins: Krit1 (Krev interaction trapped-1), OSM (Osmosensing scaffold for MEKK3 or malcalvernin), and PDCD10 (Programmed cell death 10). We have found that all three CCM proteins interact with each other and form a signaling complex in the cell. PDCD10 stands out among these proteins because of its extremely conserved amino acid sequence from invertebrates to mammals. Mutations of PDCD10 represent about 10% of all CCM;however, the subsequent lesions are the most severe form. PDCD10 is also the only CCM protein that has no known domain or motif that would provide possible insight into function. Our long term goals are to understand how PDCD10 functions in physiologic vascular development and pathologic CCM development and to translate this basic knowledge from this CCM system to new preventive/therapeutic interventions for hemorrhagic stroke and other vascular malformations. We hypothesize that (1) PDCD10 regulates p38 activation through its interaction with OSM, and (2) PDCD10 participates in PDK1 signaling via its interactions with phospholipids, and PDK1. We further propose that these interactions are essential for endothelial migration and vessel formation.
Two aims are proposed in this study including define the role of PDCD10 in endothelial p38 MAPK activation (Aim 1) and define the functional relationship between membrane phospholipid binding of PDCD10 and signaling through PDK1 (Aim 2). Using endothelial cell line, we will examine the functional changes resulting from PDCD10 knockdown using RNAi and mutants containing site-specific mutations that impact its ability to interact with OSM, phospholipids, and PDK1. The localized interaction of complex, activation of downstream kinases, as well as endothelial migration and vessel formation will also be examined.

Public Health Relevance

Understanding and manipulating complex protein-protein interactions required for physiological signaling during angiogenesis and vasculogenesis is an important step in developing prevention and treatment for hemorrhagic stroke. These proposed studies will be one of the first to define the unknown function of PDCD10 protein. Mutations of PDCD10 gene contribute to a genetically-predisposed hemorrhagic stroke condition called Cerebral Cavernous Malformation (CCM). This work links the CCM condition to two important cell signaling cascades including p38 MAP kinase and PI3K/PDK1, and providing us to new therapeutic targets for hemorrhagic stroke.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL092338-02
Application #
7844923
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Charette, Marc F
Project Start
2009-07-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2012-06-30
Support Year
2
Fiscal Year
2010
Total Cost
$222,000
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Dentistry
Type
Schools of Dentistry
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Bencharit, Sompop; Byrd, Warren C; Hosseini, Bashir (2015) Immediate placement of a porous-tantalum, trabecular metal-enhanced titanium dental implant with demineralized bone matrix into a socket with deficient buccal bone: a clinical report. J Prosthet Dent 113:262-9
Bencharit, Sompop; Byrd, Warren C; Altarawneh, Sandra et al. (2014) Development and applications of porous tantalum trabecular metal-enhanced titanium dental implants. Clin Implant Dent Relat Res 16:817-26
Byrd, Warren C; Schwartz-Baxter, Sarah; Carlson, Jim et al. (2014) Role of salivary and candidal proteins in denture stomatitis: an exploratory proteomic analysis. Mol Biosyst 10:2299-304
Baxter, Sarah Schwartz; Dibble, Christopher F; Byrd, Warren C et al. (2014) Role of cytoskeletal proteins in cerebral cavernous malformation signaling pathways: a proteomic analysis. Mol Biosyst 10:1881-9
Edelmann, Alexander R; Schwartz-Baxter, Sarah; Dibble, Christopher F et al. (2014) Systems biology and proteomic analysis of cerebral cavernous malformation. Expert Rev Proteomics 11:395-404
Altarawneh, Sandra; Bencharit, Sompop; Mendoza, Luisito et al. (2013) Clinical and histological findings of denture stomatitis as related to intraoral colonization patterns of Candida albicans, salivary flow, and dry mouth. J Prosthodont 22:13-22
Bencharit, Sompop; Baxter, Sarah Schwartz; Carlson, Jim et al. (2013) Salivary proteins associated with hyperglycemia in diabetes: a proteomic analysis. Mol Biosyst 9:2785-97
Border, Michael B; Schwartz, Sarah; Carlson, Jim et al. (2012) Exploring salivary proteomes in edentulous patients with type 2 diabetes. Mol Biosyst 8:1304-10
Bencharit, Sompop; Altarawneh, Sandra K; Baxter, Sarah Schwartz et al. (2012) Elucidating role of salivary proteins in denture stomatitis using a proteomic approach. Mol Biosyst 8:3216-23
Bencharit, Sompop; Border, Michael B (2012) Where are we in the world of proteomics and bioinformatics? Expert Rev Proteomics 9:489-91

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