About four billion years ago, while earth was covered with a primordial soup enriched with the building blocks of life, the equal occurrence of chiral molecules (non-superimposable “left-handed” vs “right-handed” molecules) fell out of balance. As a consequence, today’s life is asymmetric.
In humans, our visceral organs such as the heart, pancreas, and intestine are asymmetrically positioned along the left-right (L-R) axis. The key sensory organelle in L-R patterning is the primary cilium, a hair-like structure protruding from the plasma membrane of most mammalian cells and believed to function like an antenna. Primary cilia and dendritic spines share key features as electric signaling organelles, including similar dimensions, high density of ion channels, and compartmentalized calcium signaling. Hence primary cilia utilize ciliary ion channels and electric signaling to “sense” directed fluid flow and orchestrate asymmetric gene expression during early development. While we have a pretty good understanding of the signals controlling synaptic transmission, the fundamental molecular mechanisms by which primary cilia sense their local environment are only poorly understood. Yet a plethora of severe human diseases such as congenital heart disease, autosomal dominant polycystic kidney disease (ADPKD), obesity, and mental retardation can be attributed to improper cilia function.
My lab studies the molecular mechanisms of how primary cilia utilize ion channels and GPCRs to sense their local environment.
Major research goals in our lab include
1) Identify the environmental signals that activate ciliary Ca2+ channels
2) Understand cilia-dependent signaling cascades governed by electric signaling.
3) Define the electric signaling within the embryonic node during early steps of establishing asymmetry.
4) Identify small molecule agonists and antagonists of ciliary ion channels as novel therapeutics for the treatment of ciliopathies such as ADPKD
5) Understand the diversity of primary cilia signaling with respect to ion channel composition.
We use a variety of different approaches including mouse genetics, RNA sequencing, cutting edge primary cilia Ca2+ imaging, electrophysiology and biochemistry.
Lab Members
Mai Nobuhara
Mito Kuroda
Kodaji Ha