Periodic Reporting for period 1 - GUIDESIGINT (Competitive assembly dynamics of the DCC receptor with its guidance cues integrates signals for cellular steering)
Reporting period: 2017-02-01 to 2019-01-31
The development of human nerve and blood vessel networks is a complex process. In part, it relies on a molecular communication hub involving the signaling protein netrin, which allows growing cells to orient themselves within a developing tissue and direct their migration patterns. A mechanistic depiction of this process underpins an understanding of our own nature, and propels our capacity for medical intervention in neural repair and cancer treatments. In this project, we explored the biophysical relationships between netrin and its binding partners as a molecular basis of cellular communication. Our ultimate goal is to translate molecular-scale discoveries to animal models, and finally to human medicine.
The human protein netrin contains binding sites for multiple partners in a complex interaction network. In particular, netrin assembles two cell receptor proteins in alternative configurations that have opposing effects on cell growth and migration patterns. We first approached this puzzle by molecular dissection, in which the role of each of three binding sites within netrin was independently clarified. Next, we discovered an additional cofactor that redistributes netrin binding propensities, acting as a molecular switch for interaction. Interestingly, this natural cofactor can also be truncated to small drug-like compounds with high potency. We are currently validating these molecular-scale biological findings in a mouse model, and in parallel determining the potential of the truncated cofactor to be used in a therapeutic setting.
Beyond the state of the art in fundamental neurobiological research, we are considering a patent application.