Machaca Lab

Khaled Machaca, PhD
Professor of Physiology and Biophysics
Senior Associate Dean for Research, Innovations, and Commercialization
+974 4492 8423
Khaled Machaca

Research Interests

Welcome to Machaca Lab!

We are fascinated by the regulation of intracellular signaling pathways under both physiological and pathological conditions in the context of the regulation of oocyte maturation, meiotic arrest, cell cycle progression and secretion. We are particularly interested in Ca2+ signaling as a ubiquitous signaling module throughout phylogeny that is critical in mediating cellular responses to various cues. In fact, Ca2+signaling is often remodeled during cellular development and cellular pathology.

Oocyte maturation in preparation for fertilization offers a classical example of remodeling of calcium signaling during development. Fully grown oocytes in the ovary are not fertilizable until they undergo oocyte maturation, which encompasses both entry into meiosis, and a cytoplasmic differentiation that includes a dramatic remodeling of the Ca2+ signaling machinery. Ca2+ is the universal signal for egg activation at fertilization and for mediating the egg–to–embryo transition. Ca2+ signaling differentiation during oocyte maturation allows the egg to produce the specialized Ca2+ transient at fertilization to initiate egg activation. Ca2+ signaling remodeling affects both Ca2+ release and influx pathways including the IP3 receptor, the store-operated Ca2+ entry, the plasma membrane Ca2+ ATPase, and the Ca2+–activated Cl- channels (CaCC). We are interested in the complex interplay between these Ca2+ signaling modules and effectors in the context of meiosis progression. We are also investigating the regulation of Ca2+ signaling pathways at the cellular level in various pathological conditions and cell types, including vascular smooth muscle cells in hypertension; breast cancer metastasis; and the role of Ca2+ signaling in regulating metabolism.

Ca2+ signals often lead to different cellular responses in the same cell. This specificity is encoded in part in the spatial and temporal features of Ca2+ signals to activate subsets of downstream effectors leading to a defined cellular response. We are investigating the mechanisms controlling this specificity by focusing on the SOCE pathway and IP3-dependent Ca2+ release. We have recently described a novel Ca2+ signaling module that allows Ca2+ signaling in the mid-range spatially, between the classically defined Ca2+ micro-domain and global Ca2+ signals that cover the entire cell. Mid-range Ca2+ signaling occurs downstream of SOCE and uses ER tunnels to transport Ca2+ to specific effectors without inducing a global cytosolic Ca2+ rise (Ca2+ teleporting/tunneling). We have shown that CaCC are specifically activated by this pathway and are currently investigating other effectors.

Another emphasis in the Lab, consistent with the focus on signaling, is on the mechanisms controlling oocyte meiotic arrest in Xenopus. Vertebrate oocytes are arrested in prophase I for extended periods of time to allow for oocyte growth before maturation in preparation for fertilization. In Xenopus, meiotic arrest is released in response to steroids, particularly progesterone. We are interested in the mechanisms controlling meiotic arrest including the role of the progesterone receptor and the cAMP pathway and their interaction with the cell cycle kinase cascades.