Download Development of drug targets for bone diseases.

NUS Graduate School for Integrative Sciences and Engineering
Research Project Write-up
Title of Project :
Development of drug targets for bone diseases
Name of Supervisor :
Valiyaveettil Suresh (NUS- Chemistry),
Li Bao Jie (IMCB)
Contact Details:
[email protected]
Short Description
One of the major illness faced by the ageing population involve bone diseases, in
particular, the formation of porous bone (osteoporosis) or brittle bone. The natural
regulation of bone growth in our body is controlled by various enzymes and other genetic
factors. We are just beginning to understand the cause and molecular pathways of many
bone diseases and looking to develop novel drug targets for such diseases.
Here, we focus our attention on the Atm-cAbl-p53 pathway in mouse
development and adult bone homeostasis. Mouse genetic studies revealed that mice
deficient for c-Abl or Atm showed osteoporosis and p53 showed osteosclerosis. These
genes regulate osteoblast differentiation and bone formation via controlling the
expression of osteoblast specific transcription factor Osterix, which was shown to be
regulated by BMPs activated canonical Smad pathway and the non-canonical
Tab1-Tak1-MAPK pathway. Mechanistic studies revealed that c-Abl phosphorylates 4
Tyr residues at the C-terminal region of BMPRIA. Defects in BMPRIA
pophopshorylation reduces the interaction between BMPRIA and BMPII but enhanced
the interaction between BMPRIA and Tab1-Tak1, leading to compromised Smad1/5/8
activation but enhanced MAPK activation. This results in a reduction of Id1 and an
elevation of p16, pre-mature senescence of c-Abl-/- osteoblast, and a defect in
osteoprogenitor expansion in vivo. Atm and p53 deficient osteoblasts also show
deregulation of BMP-Smad signaling. The present project will involve i) screening for
activators of the BMP-Smad pathway and test their potential as a target for osteoporosis
and/or cancer therapy, and ii) study the possible role of the BMPRIA-Tab1-Tak1 in
osteoblast expansion/differentiaotn, bone development, using BMPRIAfloxed, Tak1floxed,
and p38 MAPKfloxed mice
We also work on Aph2, a protein identified as a cAbl interacting protein. Recently, a
knockout mice of Aph2 was generated and found that the mice showed severe defects in
heart function and cardiomyopathy. Aph2 was confirmed to be a palmitoyl transferase
for phophoslamban, a negative regulator of Ca++ pump SERCA2A and a protein whose
mutations underlie the pathology of cardiomyopathy. In vitro study show that BMPRIA
and BMPRII can be palmotiylated on Cys180 and Cys169 respectively. Our future plan
in this area include study how palmitoylation of BMPRs regulate BMP-Smad signaling
and its biological relevance in bone development and look for other substrates for Aph2
in osteoblasts.