Open Science

Taking a cue from my colleague Attila, I will be writing my dissertation via blog. My hope is that increased exposure, however slight, will improve the clarity of my thought and strength of my research plan through helpful comments and suggestions from readers. The extra scrutiny I am compelled to give this work before exposing it to the world will also serve as an additional impetus to get it right.

As I am now beginning to look for a postdoc, it doesn’t hurt to be visible to potential employers, either.

Here’s the outline:

Investigating the role of MSCs in repair of bone.

A) MSCs and bone repair.

A.1. 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.
  • 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

B.1. 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 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 or with clinical markers of bone resorption such as plasma calcium and N-telopeptides.
  • Show that I can treat the animals in this model with the Wnt agonist 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.

About Mr. Gunn

Science, Scholarly Communication, and Mendeley

26. June 2007 by Mr. Gunn
Categories: Uncategorized | Tags: , , , , , , , , , , | 3 comments

Comments (3)

  1. Hi!

    Just happened on your blog while searching for something bone cancer related. I’m a graduate student working on osteosarcoma. I found your thesis work very interesting, and wanted to wish you luck with it. One question, you mention a small molecule Wnt agonist – is there one you already use or have used?

  2. Thanks for your question, Sam, and best of luck to you too. We’ve used several. There’s more information about it in my Stem Cells paper.

    Is this you? If so, you might want to point out that there appears to be link-spam on that site.

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