Control of Transcription in the Retina
The unique features of rod photoreceptors (phototransduction cascade, specialized and renewable outer segments, and high metabolic capacity) allow them to be lifelong single-photon detectors. But these features also make rods inordinately susceptible to environmental or genetic homeostatic disturbances – ultimately leading to retinal degeneration. There are dozens of mutations in rod-specific genes that cause inherited retinal diseases (IRDs), e.g. retinitis pigmentosa, Leber congenital amaurosis, and cone-rod dystrophy. Currently no effective treatments exist.
Therapeutic development based upon gene-specific silencing or repair is challenged by the large and heterogeneous number of IRD gene mutations. In many situations, it may be therapeutically beneficial to reduce rather than silence the expression of an IRD allele. The exploration of such approaches targeting transcription factors directly is a long-term goal of our research program.
Figure. Models of Nrl and Crx interactions based on FRET signals.
Upper Diagrams. Schematic diagrams illustrating possible arrangements of Nrl (A) and Crx (B) homodimers and Nrl-Crx heterodimer (C). The intensity of the FRET signals obtained for the various combinations (Figures 4 and 5) are illustrated as green shaded ovals, with the intensity of the color representing the relative FRET signals for the various constructs. Lower Diagrams. Speculative three-dimensional arrangement of the various domains in Nrl and Crx complexes.
–from Zhuo & Knox (2022) “Interaction of human Crx and Nrl in live HEK293T cells measured using fluorescence resonance energy transfer (FRET)”, bioRxiv 2021.10.19.465002; doi: https://doi.org/10.1101/2021.10.19.465002 .
G-protein coupled receptors and Lyme disease
Ticks transmit a large array of pathogens that lead to infections such as Lyme disease. Such vector-borne pathogens infect humans during blood feeding (hematophagy). Therefore, one approach to control transmission is to block or suppress feeding behaviors, such as the stereotyped activities of questing, attachment and ingestion. Feeding occurs in response to internal energy and water balances, and external factors of temperature, humidity and photoperiod. The neural control of sensory processing and motor system responses utilize neuropeptides and G-protein coupled receptors in signaling networks. However, there is a large knowledge gap in our understanding of neuropeptide systems in ticks.
Based upon homology with insects, we are studying three neuropeptide systems: CCHa, sulfakinin and sNPF, in Ixodes scapularis as coordinate regulators of the neural circuitry that determine feeding success. We have molecularly characterized three I. scapularis neuropeptides and their receptors and are using environmental dsRNAi approaches to silence these three NP systems in vivo to determine effects on tick feeding. The long-term goal of our research is to establish new groundwork on the neurobiology of hematophagy and to identify chemical disruptors that disturb tick feeding behaviors and reduce the transmission of pathogens – ultimately reducing the spread of tick-born diseases.
Feeding Behaviors in Ixodes
Ixodes scapularis neuropeptide systems