Associate ProfessorSonia Saad

Project Opportunities

Title: Mitochondial DNA damage, potential target to reduce the development of renal disorders induced by maternal smoking .

Summary of opportunity:

Smoking rates are disproportionately high in disadvantaged populations, particularly in emerging economies, and increasing in women of child bearing age.

Opportunity synopsis:

Epidemiological studies have shown that maternal smoking is associated with a number of adverse fetal outcomes including intrauterine growth retardation and increased risk of obesity, hypertension, chronic kidney disease (CKD) and type 2 diabetes later in life. We hypothesize that maternal smoking leads to oxidative stress and fetal epigenetic mitochondrial DNA mutations resulting in intrauterine growth retardation and predisposition to chronic kidney disease (CKD). A mouse model will be used to address this hypothesis. Interventions will be tested in both pregnant mothers and offspring changes with the aim being to prevent future renal dysfunction. The project will address two of the national health strategic initiatives which focus on a healthy start to life and chronic disease and its impact on the Australian health burden. We anticipate that our outcome will be highly relevant for the prevention of CKD in offspring from smoking mothers and will also have a potential for therapeutic interventions that will translate into clinical practice.

Project Opportunities

Title: Predicting the future risk of chronic kidney disease in offspring of obese mothers with and without type 2 diabetes

Summary of opportunity:

Chronic kidney disease (CKD) is a major health burden driven mostly by obesity and type 2 diabetes mellitus. 1/3 of diabetic patients are at risk of CKD progression for unknown reason. Symptoms of CKD are not evident until significant renal function is lost, when the condition become non curable mainly because renal biopsy is required for definitive diagnosis. The project will determine possible biomarkers for patients at risk of CKD progression using novel non-invasive diagnostic method.

Opportunity synopsis:

Chronic kidney disease (CKD) is a major health burden driven mostly by type 2 diabetes and obesity. CKD affects up to 1.7M Australians contributing to approximately 15% of hospitalisations nationally. The prevalence of end-stage kidney disease continues to increase and is not fully explained by traditional risk factors. It is unclear why only 1/3 of patients with diabetes develop CKD, and why the progression of CKD varies substantially from patient to patient, even among those with similar co-morbidities. Evidence suggests a strong link between intrauterine environment and disease programming.
Only 1/12 with kidney disease are aware they have the condition as symptoms and signs of CKD are not evident until significant renal function is lost mainly because a definitive diagnosis requires renal biopsy which can't be routinely performed in diabetic patients due to its invasive and costly nature. Hence novel biomarkers for early diagnosis or to identify patients at risk of CKD progression in a non-invasive method are needed.
We have recently demonstrated that maternal obesity is associated with increased oxidative stress and mitochondrial dysfunction in the offspring kidneys and signs of glomerular and tubulointerstitial injury which foreshadow the development of CKD. Our data also demonstrated increased renal injury in offspring from obese mothers exposed to type 2 diabetes (T2D). The current project aims to determine early diagnostic markers for CKD development in animals with T2D and predictive markers for future CKD progression in offspring born to obese mothers using a non-invasive method.

Project Opportunities

Title: Novel therapy to prevent and treat kidney fibrosis

Summary of opportunity:

Progressive kidney disease is a global health burden most commonly caused by diabetes and obesity, which are dramatically on the rise. In Australia, 1 in 3 adults are at risk of developing chronic kidney disease (CKD) which has enormous economic consequences. This project will provide a proof of concept for a new drug which not only aims to prevent/delay CKD progression but to potentially reverse progressive renal failure which is critical for the health and wellbeing of 1.8 million Australians.

Opportunity synopsis:

Kidney fibrosis is the inevitable consequence of an excessive accumulation of extracellular matrix (ECM) that occurs in virtually all chronic kidney disease (CKD) leading to irreversible end stage kidney disease. Strategies that target one pathway contributing to kidney fibrosis have failed in numerous clinical trials. Hence new agents targeting novel pathways to limit kidney fibrosis are critically needed. The proposed strategy is not dependent on inhibiting a single pathway leading to fibrosis, but rather aims to directly inhibit matrix protein cross-linking, mediated by lysyl oxidase-like 2 (LOXL2), that leads to irreversible fibrosis. We have recently demonstrated that lysyl oxidase-like 2 (LOXL2) expression is increased in human proximal tubule cells exposed to hypoxic conditions and in diabetic mice kidney. LOXL2 has been demonstrated to be overexpressed in multiple experimental models of renal fibrosis. The current project will determine whether LOXL2 inhibition can prevent and/or reverse renal fibrosis. Three models of renal injury, each of which reflect human disease will be studied. We will additionally assess the correlation of pathological change with plasma and urinary biomarkers. This will allow us to determine non-invasive markers of therapeutic efficacy in future clinical studies.

----------Current Research Projects----------

1. Exfoliated kidney cells from urine for kidney transplant monitoring: A potential opportunity?
2. Association between glycemic control and complications with concentration of urinary exfoliated proximal tubule kidney cells in people with Diabetes Mellitus.
3. SCFA biotherapy delays diabetes in humanized 1 gnotobiotic mice by remodeling mucosal homeostasis and metabolome.