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Intracellular signalling and cancer

Associate Professor F.M. Ng

Obesity and diabetes are very prevalent in developed countries and are closely associated with cardiovascular diseases which are the major cause of morbidity and mortality. However, the biochemical mechanisms involved in the development of these metabolic disorders are largely obscure and effective prevention and treatment are therefore unavailable. Recently, considerable international research interest and resources have been directed to deal with these health problems. In our research team, studies in this area continue to focus on the understanding of the aetiology and treatment of the disease, with the emphasis on the development of new pharmacotherapy from natural biomolecules.

Our investigation of the role of human growth hormone (hGH) in diabetes and obesity for the last two decades has been well recognized world-wide. Research findings from our laboratory suggest that within the hGH molecule there are distinctive functional domains for specific biochemical actions. We have identified the anti-diabetes and anti-obesity domains of the hGH molecule which are being developed as therapeutic agents for the treatment of the metabolic disorders. Currently, many biological proteins and peptides are being developed as pharmaceuticals, but the usefulness of peptide agents is generally limited by proteolytic degradation in the gastrointestinal tract and the availability of an appropriate delivery system. A series of rationales for designing small bioactive peptide analogues with increased biological potency and molecular stability has been established. There is sufficient knowledge of peptide design to synthesize metabolically stable semi-peptidic analogues, and of new biotechnology for formulation and delivery of peptide drugs.

Current research is to exploit novel prognostic biochemical approaches including including X-ray and NMR analysis for the elucidation of the activity profiles of insulin. This provides the basis for the design of insulin analogues of defined conformational requirements for the specific biological actions and the development of superpotent long-acting agonists. Such agonists/antagonists could be important for human applications. The formation and delivery of the synthetic analogues derived from the hypoglycaemic domain (hGH 6-13) of the human growth hormone molecule are being studied. The effect of these formulations on insulin resistance is being assessed at present, using euglycemic clamp technique. Studies of the molecular mechanism of the insulin-potentiating action, including the agonistic action on the signal transduction pathways of the synthetic analogues, are also underway. In obesity research, the three complementary projects currently undertaken are: (1) development of anti-obesity agents related to the lipolytic/anti-lipogenic domain of hGH, (2) investigation of the effect of subcutaneous electrotherapy in reduction of adipose tissue mass in cellulite, (3) elucidation of the role of omega()-3 polyunsaturated fatty acids on adipose tissue metabolism.

The development of anti-obesity analogues represents our immediate target to control human obesity and to minimise the associated health risks such as diabetes, hypertension and other cardiovascular diseases. The analogues will provide a potential adjunct therapy for body weight control. Structure-function studies of the potential anti-obesity analogues are in progress. In addition, investigations into the agonistic actions of the novel compounds at the level of the signal transduction pathways are also underway to elucidate the mechanism of action following the interaction of peptide with the receptor. Subcutaneous electrotherapy has been used extensively to treat cellulite, a common disorder which affects mostly women. During this treatment, electrodes are inserted subcutaneously and through these, computer generated currents are applied. The success rate of this procedure has been documented, however metabolic studies at the cellular level have not been reported and have recently begun in our laboratories. We are studying the effect of subcutaneous electrotherapy on lipid metabolism in adipose tissue. Results indicate that, acute as well as long-term treatment causes a significant increase in free fatty acid mobilisation from adipose tissue. The findings support the concept that subcutaneous electrotherapy modulates lipid metabolism by stimulating lipolysis and consequently reducing total fat mass.

Research has shown that -3 long chain polyunsaturated fatty acids (enriched in fish oils) play a vital role in reducing blood glucose and plasma triglycerides, thus preventing conditions such as atherosclerosis, thrombosis and coronary heart disease from occurring. Studies in progress aim to elucidate the mode of perturbation of fat metabolism in adipose tissue. For example, to determine if the -3 fatty acids decrease triglyceride synthesis in adipose tissue and reduce insulin resistance in muscle.

Project Areas

  1. Design and synthesis of therapeutic compounds for treatment of obesity and diabetes (Associate Professor F. M. Ng)
  2. Molecular and cellular studies of novel anti-obesity and anti-diabetes peptide analogues related to human growth hormone (Associate Professor F. M. Ng and Dr R. Gianello)
  3. Development of insulin derivatives with increased potency and prolonged bioavailability (Associate Professor F.M. Ng and Dr R Gianello)
  4. Studies of anti-obesity and anti-diabetes agents of phytochemical origin (Associate Professor F. M. Ng and Dr R. Gianello)
  5. Nutritional and pharmacological treatment of human obesity (Associate Professor F. M. Ng and Professor M. L. Wahlqvist (Monash Medical Centre ))
  6. Studies of insulin resistance in relation to obesity in sand rats (Associate Professor F. M. Ng and Professor P. Z. Zimmet)