October 2014 | ISSUE 14
In search of a novel treatment for heart failure

LKCMedicine Assistant Professor Wang Xiaomeng hopes to deliver elusive blood vessel formation agent

By Nicole Lim
Assistant Director, Communications & External Relations 

IMG_6640 (CROPPED) (Custom).jpgSince the first member of the research faculty joined the School, LKCMedicine researchers and scientists have been awarded a total of 10 national research grants worth close to $5 million for a range of research projects led by them. One of the recipients is LKCMedicine Assistant Professor Wang Xiaomeng, who received a $1.2 million National Medical Research Council Cooperative Basic Research Grant.

The grant enables her and her collaborator Professor Hong Wanjin from the Institute of Molecular & Cell Biology (IMCB) to investigate the therapeutic potential of a novel pro-angiogenic protein to treat coronary heart disease in diabetic patients.

Coronary heart disease is the second most common cause of death in Singapore and one of the leading causes of death worldwide. Depending on the severity of the disease, current treatments range from simple lifestyle changes and medication to surgery. If the disease is left unchecked or cannot be controlled with treatment, it leads to heart failure. The condition is much more common in people with diabetes, who are two to four times more likely to develop cardiovascular disease than people without diabetes.

“Coronary heart disease is more common in older people and is often associated with other complications such as hypertension and diabetes. This means that they may no longer be suitable for many of the treatments or that the treatments don’t work for them,” said Asst Prof Wang.

Asst Prof Wang’s research focuses on a novel protein, LRG1, which promotes the formation of new blood vessels, a process known as angiogenesis.

“Studies so far have shown that if we inhibit LRG1, we can reduce vascular formation in cancers and diabetic retinopathy,” said Asst Prof Wang, who is also a joint Principal Investigator at IMCB. “Now, we want to find out whether we can encourage formation of vessels by stimulating LRG1 release.”

When angiogenic targets were first identified more than a decade ago, expectations of new breakthrough treatments for ischaemic conditions such as stroke, peripheral arterial diseases and coronary heart disease were high. But despite significant investments in such research, no new treatments have emerged that deliver on this promise.

To avoid the pitfalls encountered by their predecessors, Asst Prof Wang and Prof Hong intend to use a purpose-designed animal model.

“To reduce the difference between humans and our animal model, we’ll be using older mice with induced diabetes, so that the mouse’s overall health is similar to that of a patient with coronary heart disease,” said Prof Hong.

In addition, LRG1 is involved in multiple aspects of blood vessel formation. “Previous studies have largely focused on one molecule in a single pathway, VEGF, which exerts its function mainly on endothelial cells. Our preliminary data shows that LRG1 regulates the signalling and function in both endothelial and mural cells,” added Asst Prof Wang.

The LGR1 protein encoding gene will be injected directly into the heart to deliver the treatment where it is needed. “We will manipulate the expression of LRG1 so that it will only be activated when the heart is deprived of oxygen as would happen in heart failure. This is to ensure that the treatment is released in the right place at the right time and avoids blood vessel growth stimulation in other parts of the body where we don’t want it,” said Prof Hong.

Results of this study are expected in three years. If successful, they hope that LRG1, in combination with other existing treatments, will benefit not only patients with coronary heart disease but also those suffering from other diseases caused by oxygen deficiency, such as stroke and peripheral arterial diseases.

 

Table of national research grants awarded to LKCMedicine research faculty as lead Principal Investigators:

​Grant​Awardee​Grant Title
MOE Tier 2 (July 2012)Prof Michael FerencziThe molecular basis of the stretch response in skeletal and cardiac muscle
​MOE Tier 2
(Feb 2014)
Asst Prof Wang Xiaomeng​Role of LRG1 regulated TGFβ signalling in melanoma progression and metastasis
​MOE Tier 1 (Mar 2013) ​Prof Michael FerencziThe role of titin mutations in modifying the contractile performance of cardiac myofibrils
Asst Prof Wang XiaomengLeucine-rich alpha-2-glycoprotein 1 (LRG1) as a novel modulator of TGFβ signalling in cancer
MOE Tier 1 (Jan 2014) ​ ​ ​Prof Dean NizeticOptogenetic stimulation of neurons derived from human induced pluripotent stem cells for next-generation disease-modelling of neurological conditions with defective synaptic plasticity and accelerated neuronal ageing
Prof Balazs GulyasPharmacologically induced autophagy in a "humanised" small animal disease model as a possible preventive therapy for neurodegenerative diseases
Asst Prof Yusuf AliUnravelling the molecular mechanism of apolipoprotein CIII-mediated pancreatic beta-cell apoptosis in Type-2 diabetes
Asst Prof Navin VermaCharacterisation of GSK3beta pathway in T-cell migration: Implications for novel immuno-modulatory therapies
NMRC-CBRG (Nov 2013)Asst Prof Wang XiaomengLeucine rich alpha-2-glycoprotein 1 as a novel therapeutic target in ischemic cardiovascular diseases
A*STAR-NHG-NTU Skin Research Grant 2013Prof Artur Schmidtchen with Dr Victor Nurcombe (IMB, A*STAR)Assessing novel carbohydrates for skin wound repair


Acronyms:
MOE – Ministry of Education
NMRC – National Medical Research Council
CBRG – Cooperative Basic Research Grant