Tamara Alliston

Research Interests

Regulation of Skeletal Cell Differentiation and Matrix Quality

Research Summary

One in three American adults suffer from arthritis symptoms, yet the molecular basis of this degenerative skeletal disease remains unclear. Our research focuses on the molecular pathways controlling mesenchymal stem cell differentiation, how these pathways function in normal skeletal tissue, and how they can be harnessed to repair tissue damaged in degenerative skeletal disease. To answer these questions we combine molecular, cellular, physiologic, and materials science approaches. I believe this interdisciplinary approach will lead to the identification of targets to prevent skeletal disease or to improve skeletal repair.

Current Research Goals:

1. Understand the mechanisms by which TGF-beta regulates osteoblast and chondrocyte differentiation
TGF-beta is a key regulator of osteoblast and chondrocyte differentiation. Abnormal TGF-beta signaling has been implicated in a number of human skeletal d! iseases. Likewise, mouse models with alterations in TGF-beta signaling exhibit a variety of skeletal defects, including osteoarthritis and osteoporosis. Cell-based studies are used to identify signaling pathways and transcriptional regulators downstream of TGF-beta in the control of cell differentiation. In vivo studies allow examination of the role of these pathways in bone and cartilage.

2. Understand the regulation of bone matrix material properties
With the promise of harnessing stem cells to generate skeletal tissue, remains the challenge of creating tissue of sufficient mechanical quality. Bone matrix material properties, in addition to bone mass and architecture, determine the ability of bone to resist fracture. However, very little is known about the mechanisms that control the material properties of skeletal matrices. We have recently identified TGF-beta as a key regulator of bone matrix mechanical properties and composition. We now aim! to identify the pathways by which TGF-beta controls these properties. One goal is to identify therapeutic agents that may improve the material properties of skeletal matrices, and consequently, improve or protect skeletal function.

3. Understand the role of bone matrix quality in bone disease-associated hearing loss
The composition and mechanical properties of bone are critically important for normal hearing. This is made evident by the hearing loss associated with several bone diseases. We are testing the hypothesis that hearing loss in these bone diseases results from defective matrix material properties of ear bones. These studies will provide insight into the role of bone matrix in auditory structure and function.

Selected Publications

Balooch G, Balooch M, Nalla RK, Schilling S, Filvaroff EH, Ritchie RO, Marshall GW, Marshall SJ, Derynck R, and Alliston T. (2005) TGF-beta signaling regulates the mechanical properties and composition of bone matrix. P.N.A.S. 102:18813-8.

Kang J.S., Alliston T, Delsto! n R, and Derynck R. (2005) Repression of Runx2 function by TGF-beta through recruitment of class II histone deacetylases by Smad3. EMBO J. 24:2543-55.

Alliston T, Derynck R. (2002) Interfering with bone remodelling. Nature. 416:686-7.

Alliston T, Choy L, Ducy P, Karsenty G, Derynck R. (2001) TGF-beta-induced repression of CBFA1 by Smad3 decreases cbfa1 and osteocalcin expression and inhibits osteoblast differentiation. EMBO J. 20:2254-2272.