|Basic Science Research|
The focus of the Ferreira laboratory is to understand the integration of signaling and trafficking pathways and how of such pathways relay environmental cues across subcellular compartments and cellular systems in mouse and disease models. Central to our interests is the discovery of the role of such pathway networks in the modulation of aging and disease processes leading to neurodegeneration and other human maladies. Although not exclusively, we employ extensively the mammalian visual system in our studies because i) it comprises a neurocircuitry, whose cellular and subcellular architectures and function of various classes of neurons are diverse, but relatively well defined, ii) the developmental fate and survival of distinct classes of neurons are highly dependent on the coordination of environmental cues relayed to multiple but still poorly understood molecular and subcellular processes, iii) aging and a large number of non-syndromic and syndromic diseases with poorly defined molecular pathogenesis affect strongly the visual system and often lead to the death of selective retinal neurons, iv) the retinal system is highly amenable to a wide range of interdisciplinary and noninvasive experimental manipulations and finally, v) the integration and regulation of molecular processes in the visual system can be compared and applied to other neuronal and non-neuronal systems that use similar molecular components, but under distinct regulatory mechanisms.
Currently, the laboratory employs two multifunctional and dynamic protein complexes assembled by two scaffold proteins to probe the processing of the integration of signaling and trafficking pathways in neuronal systems and several disease processes. They comprise the multisubunit complexes assembled by the Ran-binding protein 2 (RanBP2) and the retinitis pigmentosa GTPase regulator-interacting protein-1 (RPGRIP1).
Paulo A. Ferreira, PhD
Departments of Ophthalmology
and Molecular Genetics and Microbiology
AERI Bldg., 5th Floor, Room 5002
Duke Eye Center
2351 Erwin Road, DUMC 3802
Durham, NC 27710
The RanBP2 is a large pleiotropic and vital protein, which mediates the dynamic assembly of a heterogeneous protein complex implicated in the regulation of nucleo-cytoplasmic and microtubule -based intracellular trafficking pathways, protein homeostasis and biogenesis, modulation of protein-protein interactions (e.g. sumoylation), mitochondria and metabolic functions, and control of cell division. Ongoing studies support that RanBP2 acts as a "signal integrator" of multiple pathways conveying signals and movement of cargoes between various subcellular compartments. Interdisciplinary and complementary approaches with genetically modified mice, cell-based and biochemical assays, are employed to investigate the molecular, physiological and pathological roles of selective crosstalk pathways controlled by RanBP2 and its partners in neuronal function and survival, and various disease processes. The outcome of these studies are also providing novel mechanistic insights into the RanBP2-mediated regulation of fundamental molecular and subcellular processes, such as the ubiquitin-proteasome system and kinesin-mediated trafficking activities, in normal and disease states.
The RPGRIP1 is directly implicated in the molecular pathogenesis of X-linked retinitis pigmentosa type 3 (XlRP3) and Leber congenital amaurosis (LCA). These are devastating eurodegenerative disorders leading to blindness and that may serve as a paradigm to the understanding of other neurodegenerative diseases. RPGRIP1 was identified by my laboratory as a direct molecular partner of the XlRP3 gene product, RPGR. Further studies have determined that RPGRIP1 comprises a signaling interactome, which is vital to the function and morphogenesis of photosensory neurons. The deregulation of the RPGRIP1 signaling complex by mutations in genes encoding its components underlies multiple diseases processes in the human.