I’m going to be doing some traveling this month, so I’ll be using Google Documents to edit my dissertation.

Google Notebook has a nice feature where it will republish the entry to your blog when you edit it in Google Notebook. I’ve never tried this feature out before, and I hope it works like I would expect, in other words, replace only the content edited, and not add a new post.

We shall see. The outline follows:

Prospectus for Research

William Gunn

Investigating the role of MSCs in repair of bone.

A)MSCs and bone repair.

MSCs contribute to bone repair by proliferating under the influence of Dkk1 and then undergoing osteogenesis to effect remodeling at the site of injury.

  • Dkk1 is produced by MSCs at low density.

  • IL6 is produced by undifferentiated, dividing MSCs.

  • MSCs express LRP6 and Kremen1 receptors.

  • Radiolabeled Dkk1 is taken up by MSCs.

  • Recombinant Dkk1 promote proliferation of MSCs and blocks differentiation as measured by calcium accumulation assayed by either Alizarin Red or arsenazo III, or by expression of membrane-associated alkaline phosphatase.

  • Inhibition of Dkk1’s effects on MSCs with 6-Bromoindirubin monoxime(BIO), a GSK3β inhibitor, allows MSCs to continue to differentiate in the presence of Dkk1.

B)The interaction between MSCs and bone cancer

Dkk1 is secreted by myeloma cells, which produce osteolytic lesions that are resistant to remodeling.

  • The lesions occur due to an osteoblasts deficit. Osteoclasts are normal, and more active or numerous than in normal patients.

  • The IL6 that is secreted by MSCs is a strong growth factor for myeloma cells.

  • MSCs from myeloma patients are significantly different from normal MSCS.

  • Inhibition of the effects of Dkk1 with a small molecule, well tolerated, Wnt agonist such as BIO may prevent the changes to MSCs brought about by multiple myeloma, and may make lesions susceptible to remodeling again.

  • An animal model for multiple myeloma, wherein human myeloma cells are administered to a immundeficient mouse, causes bone resorption and tumor formation.

C)Proposed Future experiments.

  • Show that animals who develop tumors have a bone repair defect.

  • Show that Dkk1 is produced by the tumors in vivo, and is correlated with the magnitude of the defect.

  • Show that I can treat the animals in this model with BIO and reduce the size of tumors and incidence of osteolytic lesions, and that MSCs derived from these animal are different in a similar fashion to the MSCs derived from myeloma patients.


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