Andras Kapus | Unity Health Toronto
Critical molecular switches in renal fibrogenesis
Lay Abstract
Background: Chronic kidney disease (CKD) is characterized by the gradual loss of kidney function. This is a common and devastating condition, affecting 12% of Canadians. Currently, there is no effective therapy to halt or reverse this process. The final stage of CKD necessitates transplantation or dialysis. The limited availability of transplantable kidneys, the significant complications of both interventions, the extremely high cost (e.g. for dialysis ˜ $100,000/year/patient), the loss of active years and, most importantly, the unsurmountable human suffering signify a major need for finding new therapies that stop disease progression. The most common causes of CKD are diabetes and high blood pressure, i.e. very common conditions, which induce kidney injury and chronic scarring or fibrosis. It is therefore imperative that we find new therapies to lessen, halt or even reverse kidney fibrosis. To achieve this goal, we have to understand how the disease develops. Fibrosis is essentially a derailed healing process in response to chronic cellular stress or injury. While the body initially attempts to restore tissue integrity (adaptive phase), eventually the abnormal or exaggerated response to injury leads to excessive scar formation and destruction of organ architecture and function (maladaptive phase).
The balance between healing and chronic disease depends on proper molecular switches: these first should be tuned on to ensure regeneration, but then turned off to prevent excessive scarring. Both normal and abnormal regeneration are brought about by changes in gene expression. Activation of genes is regulated by so called transcription factors (TFs). Thus, we have to understand how TFs work and collaborate during normal healing and fibrosis. Our previous research has identified the central role of a TF, called MRTF, in fibrosis. Recent studies point to the role of yet another TF, called Sox9. Moreover, our preliminary data suggest that these factors can interact and may influence each other’s action. However, it remains unclear how this interaction occurs, how it affects the development of fibrosis, and what role(s) it plays in the switch between healing and scarring.
Purpose: The overarching goal of this research is to understand the role of critical regulators of gene expression in kidney fibrosis. We seek to know how the interaction of two healing/fibrosis-regulating TFs impact on these processes. Ultimately, this knowledge will allow us to determine how and when to target these TFs with drugs to lessen fibrosis and promote healing.
Methods: We will use a variety of molecular, cellular and animal model systems to characterize the interactions between MRTF and Sox9. We will investigate how these factors associate and how they influence each other’s production, localization within the cells, and their action in gene expression. To assess their impact on each other and on fibrosis, we will characterize their interactions or inhibit/eliminate them by various means in vitro in kidney cell cultures. In addition, we will use mouse models of kidney fibrosis, and determine how their knockdown/absence affects the development and severity of the disease.
Anticipated outcome: These studies will provide fundamental new insights into the molecular underpinning of kidney fibrosis. They will uncover the interplay between two important proteins with key roles in fibrosis. They will also inform us about critical molecular switches that determine disease progression and maladaptive responses. Ultimately, they will help us identify potential therapies that can efficiently treat this currently unstoppable disease.
Patient Engagement: The primary nature of these studies belongs to the domain of fundamental science. However, in addition to publishing our data in scientific journals, we will organize reach-out sessions to highlight our goals and results for CKD patients as well. We can get excellent help for this endeavor both from the St. Michael’s Hospital and from the Kidney Foundation of Canada. We wish to communicate how basic science strives to improve the conditions and prognosis of people living with CKD.