Samuel Rowbotham, PhD

Underdeveloped lungs are among the leading causes of death of newborn infants. One lung disease where this occurs and is caused by gene mutations is congenital diaphragmatic hernia (CDH). Some of the genes which are mutated in CDH are active in particularly important cells known as stem cells. We will study two of those genes, called KMT2D and KDM6A, and test how they work in lung stem cells, which are essential for the growth and development of the lungs. We will use mice where we can delete these genes just in certain lung cells, as well as lung stem cells that have been derived from CDH patients and those without lung disease. By learning why lung stem cells need these genes we can go on to design and evaluate new treatments that will stimulate the stem cells of underdeveloped lungs to grow and mature them. This would have a wide impact on many infants and children suffering from poorly developed lungs.

Update:

We have studied two genes, KMT2D and KDM6A, implicated in congenital diaphragmatic hernia (CDH), the leading cause of underdeveloped lungs. We discovered that a drug blocking a gene that works against KMT2D/KDM6A can partly fix the problems with how CDH patient stem cells develop into specialized cells. We have also found that KMT2D mutant mice have severely underdeveloped lungs, as we observe in CDH patients. These lungs also show the same problem with stem cells differentiating into specialized cells which we have observed in CDH patient stem cells. This means that our mouse can replicate the underdeveloped lungs of CDH and may also be used to test new treatments for underdeveloped lungs.