Sunday, May 18, 2025
5/18/2025
Solute Transporters and Retinal Health - Abstract Glucose is the primary metabolic substrate of the retina, and increasing evidence implicates glucose deficiency in the progression of retinitis pigmentosa, age-related macular degeneration, and other blinding disorders. Understanding how glucose and lactate support photoreceptor health and function is essential for developing new treatment strategies to prevent vision loss. To interrogate how glucose deprivation impacts the adult retina, we have generated mouse models in which Slc2a1 deletion from RPE or rods is controlled by tamoxifen-inducible expression of RPE65 Cre (Glut1flox/flox; RPE65CreERT2; 'RPE-i∆Glut1') or PDE6G Cre (Glut1flox/flox; iPde6gCreERT2; 'Rod- i∆Glut1') respectively5). The proposed studies will determine whether the RPE spares glucose for the neural retina or utilizes glucose for functions essential to photoreceptor support. We will determine how the high levels of GLUT1 expression in the RPE are regulated and if posttranslational modifications is regulate glucose transport activity in the RPE and photoreceptors. We will test whether the inner retinal vessels can support photoreceptors by restricting glucose transport across the outer blood-retinal barrier (RPE) or glucose uptake across the rod cell membrane. These studies will advance the field of retinal metabolism and provide fundamental insights into our understanding of vision health and function. To accomplish these goals, we will: Aim 1: Test the hypothesis that the RPE does not spare all the glucose for the outer retina and requires some glucose to support its biosynthetic and phagocytic activities. Aim 2: Determine whether glucose transported across the outer blood-retinal barrier is essential for maintaining the structure and function of rod and cone photoreceptors. It has been generally accepted that the high rate of metabolism of photoreceptors is supported by glucose and other nutrients transported by the RPE from the choriocapillaris to the outer retina. However, to date, no studies have directly tested this hypothesis. By interrupting trans-RPE glucose transport, the RPE-iΔGlut1 mouse provides a unique model system directly test the hypothesis that the outer but not the inner blood-retinal barrier supports rod and cone survival. Aim 3: Determine how selective glucose deprivation in rod photoreceptors impacts their structure, function, viability, and metabolism. GLUT1 is the primary glucose transporter expressed in rods. We will use our novel Rod-iΔGlut1 mouse line, in which GLUT1 is conditionally deleted from adult rod photoreceptors, to define glucose's critical roles in supporting rod activity and viability. We will use a multi-omics approach to investigate how glucose deprivation alters rod metabolism, whether these changes occur in the aged retina, and how metabolic dysfunction of rods impacts cone function and survival. Completions of these studies, we will have a integrative picture of how GLUT1-mediated glucose transport supports the adult RPE and rod photoreceptors.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).