Calcium Signaling in Health & Disease Group
The Calcium Signaling in Health and Disease Group conducts research in four interconnected areas: Regulated Protein Trafficking, Ca2+ Nanodomains, Immune Responses, and Respiratory Disease. The general biological principles behind these projects may apply to different systems in different species.
Regulated Protein Trafficking
CRAC channels open when the Ca2+ levels inside the endoplasmic reticulum (ER) falls. Recent work has established that upon store depletion, the ER Ca2+ sensor protein STIM1 forms multimeric complexes which then migrate across the ER membrane to specialized regions just below the plasma membrane. Here, they bind to and open Orai1 proteins, which are the pore-forming subunits of CRAC channels. The group hopes to answer the following questions: How STIM1 moves across the ER, how ER apposition to the surface membrane is organized, and how two proteins in two different membranous compartments interact with another.
Ca2+ Nanodomains: The Heart and Soul of a Ca2+ Signal
The group discovered that spatially restricted Ca2+ signals, called Ca2+ nanodomains, that extend just a few nanometers from an open CRAC channel can activate gene expression in the nucleus located several micrometers distant. Team members want to know how high is this local Ca2+ and how is it decoded by the cell and then relayed to the nucleus. Ca2+ nanodomains generated by different types of Ca2+ channel activate different cellular responses. Clearly, the channels talk to different signaling partners. What determines the local neighborhood of a channel and can specific local networks be targeted from a therapeutic perspective?
Much of scientists’ understanding of how cells respond to external signals has been extracted from studies on single cells, stripped of extraneous complexities and external inputs. Such investigations have defined the fundamental principles of Ca2+ signaling. But how Ca2+-dependent conversations occur between different cell types in an intact physiological system is unclear. The group studies immune responses in animals using high resolution imaging techniques. These methods are combined with molecular manipulations to better understand how Ca2+-dependent responses unfurl in vivo and how these are hijacked in diseased states.
Group members investigate how Ca2+ signals are altered in respiratory disorders, including those that affect both upper and lower airways, such as nasal polyposis/allergic rhinitis and asthma, respectively. Parekh and his group have found that specific allergens derived from the house dust mite are robust activators of CRAC channels in the key cell types associated with the pathogenesis of asthma. They focus on how allergens activate the channels and use molecular approaches to dissect out the underlying signaling pathways. By identifying the mechanisms involved, a major long-term goal of the group is to identify drugs that target these pathways for therapeutic use in asthma and related chronic inflammatory disorders.