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Faculty Anne M. Delany
Assistant Professor of Medicine
860-679-8730
adelany@uchc.edu
Areas of Interests:
We are interested in understanding how components of the extracellular
matrix regulate the behavior of normal bone cells and cancer cells. We
are using the matricellular glycoprotein osteonectin or SPARC as a
paradigm for these studies since this protein can modulate cell behavior
as well as play a structural role in the matrix. Osteonectin is widely
expressed in areas of active remodeling and cellular stress in multiple
organ systems. We found that osteonectin is critical for the maintenance
of bone mass, and our studies are now focused on understanding how this
matrix component, abundant in bone, regulates cell fate and survival in
the skeleton. Further, bone-derived osteonectin is a chemoattractant for
prostate carcinoma cells, and the skeleton is a preferential target for
prostate carcinoma metastasis. Importantly, increased expression of
osteonectin in tumor cells or within tumor stroma is generally
associated with poor prognosis. We are dissecting the contribution of
osteonectin expressed by tumor cells themselves and within the tumor
stroma on prostate carcinoma development and metastasis. Additional
studies are aimed at understanding the tissue-specific regulation of
osteonectin by microRNAs (miRNAs). Our data indicate that the proximal
portion of the osteonectin 3’ UTR contains a dominant motif, regulated
by miRNAs, responsible for directing cell type-specific repression of
osteonectin expression. Our research makes use of both novel animal
models and in vitro models.
Lab Rotation Projects:
Students with their own questions on how the extracellular matrix
modules cell function are welcome. Projects already available in the lab
include:
1. Determine how osteonectin supports the survival of bone cells.
This project will involve the exploration of pathways involved in
osteoblast survival under multiple stresses, and determination of which
domains of the osteonectin molecule are responsible for the promotion of
survival. Standard molecular biology techniques and transduction of
cells with retrovirus containing expression constructs will be employed.
2. Determine the impact of osteonectin, in the context a 3D bone
matrix, on the behavior and survival of metastatic prostate carcinoma
cells. This project will involve the synthesis of defined bone
matrices in vitro and the evaluation of prostate carcinoma cell
survival, mobility, and gene expression as the cancer cells interact
with the synthetic matrices. Standard molecular biology techniques and
confocal microscopy will be employed.
3. Characterize the tissue-specific regulation of osteonectin by
miRNAs. This project will involve transfection of
luciferase-osteonectin 3’ UTR chimeras into various cell types, to
determine motifs important for regulation. RNA mobility shift assays (REMSA)
will be used to map trans-acting factor interacting domains and the
activity of specific miRNAs of interest will be knocked down using
modified decoys.
4. Compare the role of osteonectin expressed by tumor cells with that
expressed by tumor stroma or within the extracellular matrix on the
progression and metastasis of prostate carcinoma in vivo. This
project will involve the analysis of wild type and osteonectin-null mice
expressing the SV40 T antigen in the prostate, which causes prostate
carcinoma. Wild type and osteonectin-null prostate carcinoma cell lines
will be generated and their growth in nude mice will be compared. Cell
lines will be further characterized in vitro and used in reciprocal
transplantation models in vivo to dissect contributions of tumor cells
vs. host microenvironment on growth and metastasis.
Visit the Center For Molecular Medicine webpage:
http://cmm.uchc.edu/index.html
Selected Publications:
Boskey A.L., Moore D.J., Amling M., Canalis E., Delany A.M. Infrared
analysis of the mineral and matrix in bones of osteonectin-null mice and
their wild type controls. J. Bone Miner. Res. 18:1005-1011, 2003.
Delany, A.M., Kalajzic, I., Bradshaw A.D., Sage, E.H., Canalis, E.
Osteonectin-null mutation compromises osteoblast formation, maturation,
and survival. Endocrinology 144:2588-2596, 2003.
Sciaudone, M., Gazzerro, E., Priest, L., Delany, A.M., Canalis, E.
Notch 1 impairs osteoblastic differentiation. Endocrinology
144:5631-5639, 2003.
Delany A.M., Amling M., Priemel M., Howe C.C., Baron R., Canalis E.
Osteopenia and decreased bone formation in osteonectin-deficient mice.
J. Clin. Invest. 105:915-923, 2000. |
