Polycystic Kidney Disease: A Disorder of Glomerulotubular Synchronization
Abstract
Overall Program: Overarching Challenge: Autosomal Dominant Polycystic Kidney Disease (ADPKD) runs in families and primarily affects the kidneys and liver. The disease causes abnormal growth of fluid-filled sacs (cysts) in the kidney and liver that get larger over decades. People affected with this disease develop a number of symptoms that include high blood pressure, fullness and pain in the abdomen, and chronic kidney failure that eventually leads many patients to need either dialysis or kidney transplantation. Over 600,000 people are affected by this disease in the United States. Currently, there is only one approved therapy for ADPKD, tolvaptan, and it only works to slow cyst growth modestly. In recognition of this, the Defense Health Agency considers Polycystic Kidney Disease (PKD) as both a PRMRP topic area and as a 2020 Area of Encouragement. Background: The genes mutated in ADPKD have been identified and much basic science research has been done to improve our understanding of what happens during cyst development and growth. But those studies have predominantly focused on understanding how abnormal rates of tubular cell proliferation are driving the cyst growth, and treatments that limit the machinery of cell proliferation (such as cancer chemotherapy) have many concerning side effects when taken over decades. The current proposal was developed from a different perspective and we believe can provide highly PKD-specific therapeutic options to slow or even reverse cyst growth. Data from our group shows that tubules normally grow as we do, and that their growth is carefully regulated so that the size of the tubule is perfectly matched to the number of cells that are needed to handle the increasing amount of fluid delivered to them. We call this appropriate tubular growth response Glomerulotubular Synchronization. We have found that the polycystin proteins serve as the brakes for that normal growth response, and in their absence the tubule diameter expands more rapidly than the amount of cells in the tubule, leading to the formation of cysts. Our second important discovery is that re-expressing the polycystin protein in a tubule that has already begun to form a cyst leads to nearly complete regression of the cyst and brings the tubule back to a normal size and shape. This amazing finding opens the door for the development of therapies that would not only prevent new cysts, but also shrink enlarged tubules back to their appropriate size. Research Plan: Based on these findings, we have assembled a team of experts in ADPKD research and biomedical engineering in order to determine the specific events that normally regulate synchronous tubule remodeling, to define how the loss of polycystins leads to the loss of synchrony between tubule remodeling and tubular cell proliferation, and to identify how those events can be therapeutically targeted. Project 1, headed by Dr. Cantley, will study the events that remodel the support proteins around the tubule (the basement membrane) so that the tubule can enlarge or contract, and the local factors that synchronously control the cell proliferative response to keep the tubule matched to the cells. Project 2, headed by Dr. Somlo, will focus on the role of a protein in the cell nucleus, Glis2, in promoting GTS and cyst expansion, and the ability of reintroduced polycystin expression to stop this response and promote regression of the cysts back to normal tubules. Project 3, led by Dr. Crews, will identify new compounds capable of targeting Glis2 for degradation in order to pharmacologically slow or prevent cyst growth as a potential new therapy for ADPKD. Project 4, headed by Dr. Caplan, will explore the signals inside the cell that connect the external sensor (polycystins in the cilia) to the tubule remodeling events, and is designed to identify tubular cell-specific pathways that control the synchronous changes in tube size and shape. To model these complex events in a controlle
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110739
Entities
People
- Lloyd Cantley
Organizations
- United States Army
- Yale University