OBJECTIVE. Bladder cancer is the 5th most common cancer, yet it remains understudied and we are only now making strides in understanding the molecular make-up of this cancer. Recently we and others have discovered that loss of the cell surface receptor Notch-1 drives growth of some bladder cancers, while increased Notch-2 activity drives other bladder cancers. Here we aim to determine how Notch-1 and Notch-2 can lead to such differing effects on cancer growth even though they share many features in common. In addition we aim to design a new drug to inhibit Notch-2 specifically.
SPECIFIC AIMS. To address these objectives, we propose three specific aims:
In our Aim #1 we will create a mouse model that over-expresses Notch-2 specifically in the bladder and we expect this will cause bladder tumours to form.
In our Aim #2 we will use advanced techniques to study the differences between Notch-1 and Notch- 2 signaling that make them have such different effects. Here we will especially investigate how each Notch protein controls the reading of genes in the cell nucleus.
In the Aim #3 we will develop a new small molecule inhibitor of Notch-2 using computer-aided drug design.