Research

Research

The Marciano laboratory investigates fundamental aspects of kidney development and regeneration, in both health and disease.

Cellular and molecular mechanisms of tubule formation and regeneration

A fundamental question in developmental biology is: How do a group of cells orchestrate the complex changes, including proliferation, migration, sorting, and differentiation to form a polarized tubule? Tubule formation is essential to the normal development of many organs including blood vessels, lung, pancreas and kidney. Congenital defects in tubule formation lead to a variety of significant human diseases, especially in the kidney. We are interested in discovering the basic cellular and molecular mechanisms that drive early tubule formation and understanding how these same mechanisms promote tubule repair by studying these processes in the developing embryo and in regenerating tissue. Gaining additional knowledge of how tubule formation occurs will shed light on how some of the congenital renal disorders arise, and may be important in acquired renal diseases of tubules such as polycystic kidney disease.

Generating a single, continuous lumen is essential to tubule function. Currently, we have focused our studies on the role of cell-cell adhesion complexes, particularly those proteins comprising the adherens junction. We have proposed the first model for how lumen formation occurs in vivo within the nephron tubules of the kidney and have identified some of the key proteins involved in this process. Significantly, we have identified multiple genetic models in which lumen continuity is disrupted. For example, mice lacking Afadin, a nectin adaptor and Rap1 effector, have defects in establishing an apical surface and forming a continuous lumen. We have also identified separate genetic models, such as mutation of p120 catenin, in which lumen diameter is increased, leading to cystic tubules. Our studies have revealed that many of the basic mechanisms of tubulogenesis are conserved, with similarities between kidney tubules and those from other organs, such as the pancreas. We are now tackling questions about how these mechanisms function in tubule repair and regeneration.

Some of the basic questions we are interested in include:

  1. How is apical-basal polarity and lumen formation initiated in a tubule?
  2. How is lumen continuity generated and maintained?
  3. What determines tubule length and width and what modifies this?
  4. How are cells within a tubule sorted to form proximal, medial, and distal domains?
  5. How do mechanisms of tubule regeneration compare to tubule development?
  6. Does enhancement of developmental pathways aid in tubule regeneration?

Mechanisms of renal glomerular formation and function

A second focus of the laboratory is the development and function of glomeruli, the filtration units of the kidney. Defects in glomerular structure and function are the most common cause of renal failure in adults, and underlie common types of kidney disease, such as diabetic kidney disease. We have concentrated on the interaction of a specialized pericyte called the mesangial cell with the glomerular basement membrane. To date, few studies have examined these interactions, despite the fact that mesangial cell function is disrupted in several human renal diseases including diabetic nephropathy. Thus far, we have identified a ligand-receptor pair between the glomerular basement membrane and mesangial cells that forms a unique adhesion structure. When this adhesion is disrupted, it causes a glomerular pattern of injury similar to the histological changes observed in many types of human glomerular diseases. Ultimately, we expect our studies to give insight into glomerular development and the dysregulation of glomerular function that occurs after damage.

Some of the basic questions we are interested in include:

  1. How do mesangial cells interact with the glomerular basement membrane?
  2. How do mesangial cells contribute to glomerular structure and function in development and in maintenance?
  3. How does disruption of mesangial function cause glomerular disease? What are the secondary effects on other cell types?
  4. Are there ways to limit glomerular injury by altering mesangial cell function?