Dr Indira Prasadam
|Recipient:||Dr Indira Prasadam|
|Intended department:||Institute of Health and Biomedical Innovation, Queensland University of Technology- Funded by Arthritis Queensland|
Osteoarthritis (OA) is the most common cause of pain and disability in Australia, affecting 1 in 4 Australians. OA is estimated to cost our health care system >$4 billion annually. Currently, a total knee or total hip replacement is the only solution for OA patients. These solutions are expensive and the artificial implants have a limited lifespan of 5-8 years after which a revision surgery is required. Obesity is a well-established risk factor for OA. It has been estimated that up to 80% of OA cases are attributed to obesity. Studies indicate that OA could be avoided each year if body mass index (BMI) was kept below 25 throughout adulthood. There is currently an obesity epidemic in the Australia, and it is crucially important to find ways to lessen the impact of obesity on OA progression. This fellowship proposal is focused on understanding the biological links between obesity and OA and finding treatments that will reduce or eliminate the contributions of obesity to the development and progression of OA. These studies will improve the clinical outcome for overweight or obese people including postmenopausal patients who tend to acquire weight due to hormonal imbalance leading to reduction in incidence and disability from this disease.
Osteoarthritis (OA) incidence in Australia has been steadily increasing at alarming levels over the past several decades. The reasons for this are not completely clear, but an increased prevalence of known predisposing factors may be promoting this trend. Several major risk-factors for OA have been identified. Among these, obesity is notable because its incidence has risen dramatically during this same period of time. OA is often diagnosed at intermediate or advanced stages of the disease, which substantially limits therapeutic approaches for its successful treatment. This indicates that the prevention of OA is probably the most promising approach to reduce OA incidence, however, the field has so far failed to deliver such an effective preventative program.
OVERALL AIM: The aim of the fellowship project is to investigate the impact of obesity on OA and evaluate anti-obesity or anti-inflammatory treatments for the prevention and/or treatment of OA.
AIM1: To determine if obesity-induced modulation of macrophage activation/polarization affects the development and progression of OA pathology.
AIM2: To determine if anti-obesity treatments, including caloric restriction with/without volunteer exercise and as well as common weight loss drugs, break the cycle of obesity, inflammation, and OA.
AIM3: To determine if fats such as lauric acid (a type of saturated fat) and plant derived phytochemicals inhibit metabolic syndrome and whether this nutritional intervention reverses obesity initiated inflammation and OA.
Over the duration of the fellowship my research is focused on researching the cellular, structural, and molecular changes that happen in joint tissues in obese animals and patient samples. From this research we made four important observations:
(1) Obesity, diabetes, hypertension, hypocholesteremia separately and together cause osteoarthritis (OA).
(2) Activation of inflammatory cascade mediated by pro-inflammatory macrophages in synovium precedes cartilage degradation in obesity models.
(3) Certain saturated fat diets (Palmitic acid and stearic acid) cause OA and certain saturated diets supress OA (Lauric acid).
(4) Obesity promotes cartilage degeneration through three pathways: activation of autophagy machinery, membrane-lipid remodelling and mitochondria induced oxidative stress.
These findings provide valuable novel insights into the development of obesity-associated OA and open up new possibilities for its control. Furthermore, I have showed that the severity of diet-induced OA changes could be attenuated by treatment with both atorvastatin and a mitochondrial targeting antioxidant. The protective effects of the mitochondrial targeting antioxidant were associated with suppression of oxidative damage to chondrocytes and restoration of extracellular matrix homeostasis of the articular chondrocytes. In summary, our data show that metabolic factors precipitates OA progression by mitochondrial dysfunction in chondrocytes, in part by increasing ROS production and apoptosis. By addressing the mitochondrial dysfunction using antioxidants, we were able attenuate the OA progression in our animal models. This approach may form the basis for novel treatment options for this OA risk group in humans.
Currently our team is working with collaborators in industry and healthcare in a multi-faceted approach to prevent OA, diagnose, it early and treat it successfully. With industry partners, our team aims to develop nutraceutical products, containing bioactive components that can reduce obesity and keep joints in a healthy state.
During the AQ fellowship tenure I have identified novel targets that are impacted in metabolic OA. The overall aim of my future research is to build on this research to identify the factors involved in OA development and progression, in order to develop effective prevention and treatments for metabolic OA. The detailed aims include identifying possible common molecular pathways for OA and metabolic syndrome (MetS) by focusing on common factors such as hypertension, obesity, dyslipidemia and hyperglycemia, and to study the role of mitochondrial dysfunction and tissue inflammation in the onset of MetS OA.
List of grants applied based in the fellowship preliminary work:
– Applied for NHMRC CDF
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