PhD by Research Programme (Dermatology and Skin Biology)

Location
Singapore
Posted
Jan 10, 2017
Closes
Jan 30, 2017
Organization Type
University and College
Hours
Full Time
Research Project Title: LRG1 in Diabetic Wound Healing and its Therapeutic Potential 

Principal Investigator:

Assistant Professor Wang Xiaomeng, LKCMedicineCo-supervisor: Professor Bernhard Boehm, LKCMedicine

Collaborator(s):
 - Assistant Professor  Xu Chenjie, School of Chemical and Biomedical Engineering, NTU
 - Associate Professor Tavintharan Subramaniam,  Khoo Teck Puat Hospital

Project Description:
We will focus on studying the role and the therapeutic potential of Leucine rich alpha 2-glycoprotein 1 (LRG1) in diabetic wound healing. We will first address the association between LRG1 and diabetic wound progression by studying the expression profile of LRG1 in wound biopsies from diabetic patients and at different stages of wound healing in diabetic mice. We will then carry out a comprehensive analysis of LRG1’s function in different types of skin cells including dermal endothelial cells, fibroblasts and keratinocytes with the presence of diabetic stimuli such as hyperglycaemia and advanced glycation end products (AGEs). This study will provide novel insights into the role of LRG1 in wound repair regulation under the normal and diabetic condition. Diabetic mouse underwent incisional/excisional wounding is a valuable tool for translational studies of the LRG1 targeted treatment. The PhD student will work closely with Prof Xiaoliu Zhang, Huston University on adenoviral associated vector (AAV) and Dr Chenjie Xu, NTU on nanotechnology based drug delivery system for LRG1 overexpression in vivo. The information extracted from this study will assist the development of novel therapeutics for non-healing chronic diabetic wound treatment.

Statement of Need:
Wound healing, a natural response to injury for restoration of tissue integrity, is a highly regulated process. In diabetic patients, this efficient and orderly process is lost and ulcers are locked into a state of chronic inflammation causing impaired wound healing. Up to 25% of diabetic patients will develop foot lesions during their lifetime and the recurrent rate of diabetic foot ulcers is 66%. While a little more than half of diabetic foot ulcers heal within 12 weeks, 13% remain unhealed a year after presentation. The non-healing ulcer can become infected and lead to amputation in the worst case. There is a 50% incidence of contralateral amputation within 2-5 years of an amputation. In Singapore alone, 700 amputations of lower extremities are due to diabetes every year (Singapore MOH report, 2001), which impose a substantial financial and social burden on the health care system. Furthermore, lower extremity amputations are generally associated with low survival rate in patients with diabetes. The 3-year post-amputation mortality rate in people with diabetes is about 50%. 
Currently, the standard of care for diabetic ulcers is to keep the wound clean and free of infection. Systemic antibiotics are used to control infections, but the estimated failure rate is high. There is no fully effective prevention of this devastating condition, which constitutes a significant unmet medical need. A better understanding of the pathophysiology and molecular mechanism of wound healing in diabetes will help the development of novel treatment strategies.

Proposed Solution:
Wound repair is a highly regulated process requiring the temporal and spatial co-ordination of different types of cells and various interacting signalling networks. Although a plethora of factors are required for successful tissue repair, TGFβ1 has undoubtedly the broadest effects. It is involved in all aspects of wound healing process including ECM production, protease expression, migration, chemotaxis, differentiation, and proliferation of different cell types, however, controversy remains as to its endogenous role.  The paradoxical actions of TGFβ1 were observed in various aspects of wound healing, which is often referred as the TGFβ switch. For example, TGFβ1 can either promote or inhibit inflammation depending upon the state of differentiation of the cell and the context of action. TGFβ1 is also well documented for its biphasic role on angiogenesis. Deciphering the role of TGFβ1 in wound healing may open a potential new avenue for diabetic wound treatment.


We recently discovered a novel angiogenic factor, namely LRG1. We showed that LRG1 exerts it function through modulating the endothelial TGFβ signalling towards the pro-angiogenic pathway. Reduced expression of LRG1 is observed in plasma of male patients with diabetes and peripheral arterial disease, a condition that is linked to delayed wound healing in diabetic patients. Interestingly, the role of LRG1 is not restricted to blood vessel formation. LRG1 is also involved in TGFβ1 mediated ECM accumulation and contractile protein expression in fibroblasts, which is critical for efficient wound closure. Targeting LRG1 may, therefore, provide an additional option for selective activation the pro-angiogenic TGFβ signalling and promote wound repair in diabetic patients.

If you have questions regarding this project, please email to Principal Investigator, Assistant Professor Wang Xiaomeng at WangXiaomeng@ntu.edu.sg

Please refer to the Lee Kong Chian School of Medicine website for programme information.