Research
Research in the lab focuses on the molecular basis of neurodegeneration. Our system of study is the neurotrophins and their receptors. Our neuronal population model is the cholinergic neurons from the basal forebrain. The human disease of our interest is Alzheimer's. We use molecular biology, biochemistry, flow cytometry, confocal and fluorescence microscopy together with histology and immunochemistry.
The neurotrophin receptors p75 and tropomyosin receptor kinase A (TrkA) play important roles in the development and survival of the nervous system. Biochemical data suggest that p75 and TrkA reciprocally regulate the activities of each other. For instance, p75 is able to regulate the response of TrkA to lower concentrations of nerve growth factor (NGF), and TrkA promotes shedding of the extracellular domain of p75 by α-secretases in a ligand-dependent manner. The current model suggests that p75 and TrkA are regulated by means of direct physical interaction; however, the nature of such interaction has been elusive thus far. Recently we found that the TMD of each receptor forms a direct complex, although the molecular mechanism is still unknown. One of the main areas of research in our laboratory is the understanding at molecular levels of how p75 and TrkA interact and regulate each other activities. In addition, the understanding of receptor tyrosine kinase RTK activation mechanism, like in the case of TrkA, is of interest to our lab. RTKs are involved in several key processes like development and growth and in several diseases like cancer.
Another area of high interest is the understanding of p75 neurotrophin receptor biological role in healthy and pathological aging. p75 neurotrophin receptor (p75NTR) was the founding member of the tumor necrosis factor (TNF) receptor superfamily (TNFRSF). p75NTR contains an extracellular domain with four cysteine-rich domains (CRD) and a death domain (DD) in the intracellular region. The DD of p75NTR is able to recruit several protein interactors. p75-DD forms homotypic symmetrical DD-DD complexes with itself and with the related p45-DD; forms heterotypic DD-CARD interactions with the RIP2-CARD domain, and forms a new interaction between a DD and RhoGDI. All these features, in addition to its promiscuous interactions with several ligands and co-receptors, the processing by α- and γ-secretases, the dimeric nature of its transmembrane domain, and its peculiar juxtamembrane region, make p75NTR a truly fascinating protein. How p75 is activated by such a diverse palette of ligands; neurotrophins, Ab or PrP? How p75, a protein with no catalytic activity is participating in such diverse biological functions as survival or cell death, cell migration and axonal growth inhibition, and neurodegeneration? Which signaling pathways p75 trigger? All these and other questions are the basis of our research.
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