Establishing Mechanistic Effects of FSGS-Causing Genetic Mutations in a Coculture Glomerular Tissue Model
Abstract
Focal segmental glomerulosclerosis (FSGS), a topic area of the Peer Reviewed Medical Research Program, describes a pattern of injury in the kidney’s filtering units, glomeruli, and remains a leading glomerular cause of kidney failure. Podocytes are highly specialized cells with unique structural qualities that wrap around the blood-capillaries of the glomerulus. FSGS arises from diverse causes, including highly penetrant mutations in genes such as INF2 (inverted formin 2) and ACTN4 (alpha-actinin-4). To date, mutations in more than 30 different genes have been shown to cause FSGS, but how these genetic mutations in various genes lead to the FSGS disease remains unclear. Recent scientific studies suggest that aberrations in podocyte structure and function are the primary factor responsible for the disease progression. This insight provides an important signature of the disease that can be used in new ways to study the effect of genetic mutations in podocytes and use them for the discovery of new drugs to treat the disease. The challenge is with the use of animal models that are less relevant to the human condition, and the variability inherent in animals or in human patient populations upon which to elucidate mechanisms and then upon which to identify treatment options. To address these current limitations, a relevant human glomerular kidney tissue system will be generated in the laboratory, with the cells carrying FSGS disease-causing genetic mutations and the corresponding normal cells. Thus, both a disease model and a normal (control) model will be established by growing the podocytes (primarily responsible for the FSGS disease) with endothelial cells. To achieve this goal, cells will be grown by an innovative approach of housing them in a native kidney-like microenvironment to guide the cell-interactions and reproduce glomeruli-like cell arrangements (podocytes covering endothelial tubes). Fluid flow will then be included in endothelial cells to simulate human physiology. Thus, by combining the approaches of bioengineering with cell biology, along with the preliminary data to show feasibility, a novel and important new strategy will be generated to provide more systematic and controllable tissue systems with which to solve many of the unanswered questions in FSGS. This will include understanding disease mechanisms, and most importantly, to learn and establish the key aspects of changes manifested in podocyte structure and function due to the genetic mutations of INF2 and Actinin-4. The additional value of the proposed system is the ability to statistically validate results as multiple systems can be run and assessed in the laboratory. Finally, the ability to use the system as a screening tool for drug discovery will be a major outcome of the planned study. The study promises to understand the effect of genetic mutations of FSGS and revolutionize the treatments for this deadly disease through the new understanding attained in the proposed studies. Broader Impact: The proposed study has the potential to lead to a widespread impact on those afflicted with the disease, as the strategy to be employed would be universal – adaptable for different forms of the disease, different stages of the disease, and also different levels of concurrent problems. Further, the system can be used to screen and identify new therapeutic treatments at any stage in the process – initiation of the disease to more mature states of the disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010320
Entities
People
- Balaji Karthick Subramanian
Organizations
- Beth Israel Deaconess Medical Center
- United States Army