Sphingosine1-phosphate (S1P) is a pleiotropic autocrine and paracrine signaling small lipid molecule that directs a wide range of biological responses through a family of high-affinity G protein-coupled receptors (S1P1-S1P5). The proposed studies will interrogate the cooperative functions of S1P1 and S1P3 subtype activation in the microvasculature to promote inflammation resolution and bone repair. Although monocyte recruitment is a critical component of the normal bone healing cascade, persistent monocyte accumulation can progress into chronic inflammation and impede recruitment and differentiation of osteoblastic progenitor cells required for tissue regeneration. Preliminary studies show that S1P1 antagonizes pathologic inflammation by preventing monocyte adhesion to activated endothelium, and that sustained delivery of receptor selective drugs targeting S1P1 and S1P3 subtypes from 3-D biodegradable polymers promotes microvascular network maturation and increases osseous tissue ingrowth in critical sized cranial bone defects. Thus, the overarching hypothesis of this proposal is that sustained delivery of pharmacological agonists targeting S1P1 and S1P3 from biodegradable polymers promotes osseous defect healing by locally suppressing monocyte accumulation to tissue implants and promoting recruitment of mesenchymal progenitor cells (MPCs) to regenerate bone.
AIM 1 will test the hypothesis that S1P1 and S1P3 act synergistically to promote mesenchymal stem cell adhesion to endothelium.
AIM 2 tests the hypothesis that selective stimulation of S1P1/S1P3 from synthetic degradable polymers prevents local accumulation of monocytes and promotes homing of mesenchymal progenitor cells in a cutaneous model of chronic inflammation.
AIM 3 tests the hypothesis that S1P1 and S1P3 modulation of inflammatory and mesenchymal progenitor cell recruitment will enhance bone healing outcomes.

Public Health Relevance

The replacement or restoration of function to traumatized, damaged, or lost organs and tissues is an increasingly significant clinical problem. It is estimated that only 24,422 received organ transplants of a possible 79,512 patients on the transplantation wait list in 2002. In addition, it is currently estimated that over 1.5 million skeletal injuries alone will require tissue graft reconstruction in the US each year, and these numbers will continue to grow as the life expectancy of the population increases. Thus, the development of effective strategies to harness inflammation for revascularization and regeneration of osseous tissue defects is a significant medical need.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE019935-05
Application #
8543695
Study Section
Special Emphasis Panel (ZDE1-RW (11))
Program Officer
Lumelsky, Nadya L
Project Start
2009-06-05
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2013
Total Cost
$339,725
Indirect Cost
$104,501
Name
Georgia Institute of Technology
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
097394084
City
Atlanta
State
GA
Country
United States
Zip Code
30332
Das, Anusuya; Barker, Daniel A; Wang, Tiffany et al. (2014) Delivery of bioactive lipids from composite microgel-microsphere injectable scaffolds enhances stem cell recruitment and skeletal repair. PLoS One 9:e101276
Ogle, Molly E; Sefcik, Lauren S; Awojoodu, Anthony O et al. (2014) Engineering in vivo gradients of sphingosine-1-phosphate receptor ligands for localized microvascular remodeling and inflammatory cell positioning. Acta Biomater 10:4704-14
Awojoodu, Anthony O; Ogle, Molly E; Sefcik, Lauren S et al. (2013) Sphingosine 1-phosphate receptor 3 regulates recruitment of anti-inflammatory monocytes to microvessels during implant arteriogenesis. Proc Natl Acad Sci U S A 110:13785-90
Das, Anusuya; Segar, Claire E; Hughley, Brian B et al. (2013) The promotion of mandibular defect healing by the targeting of S1P receptors and the recruitment of alternatively activated macrophages. Biomaterials 34:9853-62
Segar, Claire E; Ogle, Molly E; Botchwey, Edward A (2013) Regulation of angiogenesis and bone regeneration with natural and synthetic small molecules. Curr Pharm Des 19:3403-19
Huang, Cynthia; Das, Anusuya; Barker, Daniel et al. (2012) Local delivery of FTY720 accelerates cranial allograft incorporation and bone formation. Cell Tissue Res 347:553-66
Sefcik, Lauren S; Aronin, Caren E Petrie; Awojoodu, Anthony O et al. (2011) Selective activation of sphingosine 1-phosphate receptors 1 and 3 promotes local microvascular network growth. Tissue Eng Part A 17:617-29
Cui, Quanjun; Botchwey, Edward A (2011) Emerging ideas: treatment of precollapse osteonecrosis using stem cells and growth factors. Clin Orthop Relat Res 469:2665-9
Petrie Aronin, Caren E; Sefcik, Lauren S; Tholpady, Sunil S et al. (2010) FTY720 promotes local microvascular network formation and regeneration of cranial bone defects. Tissue Eng Part A 16:1801-9
Petrie Aronin, Caren E; Shin, Soo J; Naden, Kimberly B et al. (2010) The enhancement of bone allograft incorporation by the local delivery of the sphingosine 1-phosphate receptor targeted drug FTY720. Biomaterials 31:6417-24