Work will be conducted jointly at the Massachusetts Institute of Technology and at the University of Pittsburgh. Specific tasks which will be performed at each location under the direction of Wells and Griffith are summarized below. Work to be performed at University of Pittsburgh (A. Wells Laboratory): 1. Activation of select signaling pathway downstream from EGFR will be quantified in the undifferentiated MSC (Aim 1). 2. Activation of select signaling pathway downstream from EGFR will be quantified in the pre-differentiated MSC (Aim 2). 3. Production of autocrine ligands will be quantified with the MSC on various surfaces (Aim 2). 4. Differentiation of MSC while on the various surfaces into at least 3 lineages (Aim 3). Work to be performed at MIT (L. Griffith and P. Hammond Laboratory): 1. Synthesis of t-EGF substrates (Aims 1-3). Similar substrates have been successfully mailed these substrates to Pittsburgh and other labs and maintained their activity. 2. Analysis of apoptosis (Aim 1) and proliferation (Aim 2) via FACS 3. Synthesis of substrates for specialized migration/differentiation studies (Aim 3) These tasks will be coordinated by frequent telephone and electronic communications, facilitated by compatible computer software. This will promote data sharing and interpretation by all involved. All major planning will be done at semi-annual visits by the Investigators;as has been accomplished since 1994. The most recent meeting occurred in Cambridge in January 2007. This frequent visiting is further facilitated by serving on the thesis committees of each other's graduate students. Lastly, trainees will be exchanged for extended periods to learn complementary techniques and approaches;this `sharing'of trainees has been used to great advantage. Narrative Bioengineered Polymers for Parsing Cell Responses The major goal of this project is to validate an observation obtained in a model system regarding the dependence of cell interactions (adhesion, migration, proliferation) with RGD and EGFR ligands on the spatial arrangement of the ligands and extend the results to a clinically-relevant system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE019523-13
Application #
8270346
Study Section
Intercellular Interactions (ICI)
Program Officer
Lumelsky, Nadya L
Project Start
1999-09-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
13
Fiscal Year
2012
Total Cost
$342,707
Indirect Cost
$77,500
Name
Massachusetts Institute of Technology
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Alvarez, Luis M; Rivera, Jaime J; Stockdale, Linda et al. (2015) Tethering of Epidermal Growth Factor (EGF) to Beta Tricalcium Phosphate (βTCP) via Fusion to a High Affinity, Multimeric βTCP-Binding Peptide: Effects on Human Multipotent Stromal Cells/Connective Tissue Progenitors. PLoS One 10:e0129600
Krueger, Andrew T; Kroll, Carsten; Sanchez, Edgar et al. (2014) Tailoring chimeric ligands for studying and biasing ErbB receptor family interactions. Angew Chem Int Ed Engl 53:2662-6
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Rodrigues, Melanie; Blair, Harry; Stockdale, Linda et al. (2013) Surface tethered epidermal growth factor protects proliferating and differentiating multipotential stromal cells from FasL-induced apoptosis. Stem Cells 31:104-16
Jay, Steven M; Murthy, Ashwin C; Hawkins, Jessica F et al. (2013) An engineered bivalent neuregulin protects against doxorubicin-induced cardiotoxicity with reduced proneoplastic potential. Circulation 128:152-61
Wells, Alan; Griffith, Linda; Wells, Jakob Z et al. (2013) The dormancy dilemma: quiescence versus balanced proliferation. Cancer Res 73:3811-6
Rodrigues, Melanie; Yates, Cecelia C; Nuschke, Austin et al. (2013) The matrikine tenascin-C protects multipotential stromal cells/mesenchymal stem cells from death cytokines such as FasL. Tissue Eng Part A 19:1972-83
Rodrigues, Melanie; Turner, Omari; Stolz, Donna et al. (2012) Production of reactive oxygen species by multipotent stromal cells/mesenchymal stem cells upon exposure to fas ligand. Cell Transplant 21:2171-87
Wu, Shan; Wells, Alan; Griffith, Linda G et al. (2011) Controlling multipotent stromal cell migration by integrating ""course-graining"" materials and ""fine-tuning"" small molecules via decision tree signal-response modeling. Biomaterials 32:7524-31
Wells, Alan; Chao, Yvonne L; Grahovac, Jelena et al. (2011) Epithelial and mesenchymal phenotypic switchings modulate cell motility in metastasis. Front Biosci (Landmark Ed) 16:815-37

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