Research in The Alman lab focusses on five broad areas:
- Wound Healing
- Stem Cells and Neoplasia
- Cartilage and Joint Development
- Joint Degeneration and Repair
- Bone Regeneration.
The entire wound healing process is a complex series of events that begins at the moment of injury and can continue for months to years.
Our goal is to determine the role of the Wnt pathway, particularly its key molecule β-catenin, in the reconstitution of epithelial and dermal components of the skin during wound healing.
Using different genetically engineered mice designed in our lab, we investigate the fate of the cells that contribute to healing and the role of β-catenin in this process.
As part of this work, we identified a novel drug that can be used to decrease scar size, and are working to determine how it can be developed into a topical agent to use for patients.
Stem Cells and Neoplasia
Stem cells are the earliest step in the hierarchal progressive maturation to functionally differentiated cells with characteristics of self-renew and fast proliferation.
Although the concept that tumours contain a subpopulation of cells with stem cell properties has been demonstrated in a number of tumour types, little has been reported on the role of stem cells in musculoskeletal (MSK) tumours, perhaps due to lack of unique mesenchymal stem cell (MSC) marker.
In our studies, we hypothesize that MSK tumours contain a subpopulation of tumour initiating cells.
The first step in our research is to identify and isolate tumour initiating cells (TIC) from musculoskeletal tumours. Further study of this population of cells will allow for the characterization of molecular pathways regulating the development of MSK, ultimately identifying potential novel therapeutic targets.
We are also studying the role of developmentally important signalling pathways in fibrous and cartilaginous tumours.
In this work, we generated genetically modified mice that developed these tumours, and are studying how modulating the signalling pathways causes these tumours, and how this information could be used to develop potential new therapeutic approaches.
Cartilage and joint development
During development, cell fate experiments have determined that growth plate and articular chondrocytes differentiate from two distinct populations of cells.
Within the growth plate, Indian hedgehog (Ihh) regulates chondrocyte proliferation and differentiation that involves a feedback loop with the parathyroid hormone related protein (PTHrP).
We have generated transgenic mice showing that a deregulation of the hedgehog/PTHrP feedback loop during growth plate development that results in chondrodysplasias and the development of cartilage tumours; however, the role of hedgehog signalling in the differentiation and maintenance of articular chondrocyte progenitors is poorly defined.
Through investigation of transgenic mice, we hope to further identify the role of hedgehog, and other signalling pathways, on growth plate and articular cartilage development.
Joint degeneration and repair
Osteoarthritis (OA) is a degenerative disease of the joints, characterized by degradation and calcification of articular cartilage, and subchondral bone changes.
Because articular cartilage does not regenerate, understanding how joints develop may provide new insight and novel therapies for OA. Our current data suggests that Wnt, Hh, sterols and other signaling pathways involved in normal joint development may also be involved in the development and progression of OA.
Therefore, we aim to elucidate how modulating these pathways can attenuate OA pathology and enhance joint repair.
Endochondral ossification is recapitulated during long-bone repair. Although the β-catenin pathway has been investigated in the context of bone development and skeletogenesis, its role in the bone regeneration processes is not clear.
Using pharmalogical reagents, we are able to augment β-catenin signaling during bone repair and have observed substantially improved healing in various pathological conditions.
Deficiencies seen in bone regeneration with age are (in part) mediated by the β-catenin pathway. Our models which are able to “rejuvenate” aged bone regeneration do so in a β-catenin dependent manner.
Mutation in the FGFR3 gene (achondroplasia) results in augmented bone repair and cellular differentiation.
We are currently investigating the impact of FGFR3 signalling on osteoblast differentiation.
Furthermore, we are also investigating how glucocorticoids induce osteoporosis in chronic paediatric diseases such as Acute Lymphoblastic Leukemia and Duchene Muscular Dystrophy.
Insights into these pathways and diseases may offer new therapeutic options with which to enhance bone regeneration or fracture repair.