This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The heptahelical extracellular calcium sensing receptor (CASR) plays a central role in controlling systemic calcium homeostasis predominately through its effects to regulate PTH production by the parathyroid glands. CASR is coupled to G-alpha-q and G-alpha-i pathways. The biological importance and distinct function of the G-alpha-q/ Rho A and G-alpha-i pathways in mediating the actons of CASR in the parathyroid gland to regulate PTH gene transcription, PTH secretion and parathyroid gland growth and hypertrophy is not known. Because of the limitations of parathyroid cell culture models, we plan to use mouse genetic appraches to assess the function of these signalling pathways in parathyroid glands in vivo. To this end, we will use the human PTH promoter to selectively drive expression of either dominant negative inhibitory of gain-of-function transgenes to achieve respective parathyroid gland-specific disruption of constitutive activation of G-alpha-q and Rho A signaling pathways in the parathyroid glands of transgenic mice. Future studies will use similar approaches to assess the role of G-alpha-i. Assenssment of parathyorid gland function will include measurement of PTH message, PTH secretion and parathyroid cell growht. Defining the common and non-redundant function of G-alpha-q and Rho A pathwyas that are downstream of CASR activation will be useful understanding the basic biology of G-protein coupled receptor control of parathyroid gland function and may lead to the identification of new molecular targets for manipulating parathyroid gland function.
Showing the most recent 10 out of 206 publications
