About

Sarah C. W. Baker is a Clinical Professor of Law at Duke University School of Law, where she teaches Legal Analysis, Research and Writing. She joined the Duke Law faculty in 2011. Prior to her academic career, she practiced law as an associate in the litigation and employment groups at Smith, Anderson, Blount & Dorsett in Raleigh, North Carolina. Her legal practice focused on oral advocacy, legal research and writing, drafting trial briefs, motions, and appellate briefs, and serving as a member of the litigation team in complex commercial cases. She also provided counseling on labor and employment issues to employers. Baker clerked for Judge Allyson K. Duncan of the Fourth Circuit Court of Appeals after graduating with honors from Duke Law School in 2006. During her time at Duke Law, she served as a Note Editor for the Duke Law Journal, was a Hardt Cup coordinator, and was a member of the Moot Court Board. She also organized an ad hoc seminar on gender and the law and is a member of Duke Law School’s Future Forum. Baker received her BA from the University of Virginia in 2001, where she was a Jefferson Scholar and an Echols Scholar. Before entering law school, she worked as a regional manager for key accounts for The Advisory Board Company in Washington, D.C.

Research topics

• Cell biology
• Biology
• Biophysics
• Chemistry
• Neuroscience

Selected publications

• Loss of Kv8.2 in the Mouse Retina Is Associated With Altered One‐Carbon Metabolism

  Journal of Neurochemistry · 2026-03-28

  articleOpen accessSenior authorCorresponding

  Photoreceptors are highly energy-demanding neurons, and disruption of photoreceptor signaling remodels retinal metabolism and contributes to degeneration, yet the pathways underlying these changes remain incompletely defined. Kv8.2 knockout (KO) mice, a model of KCNV2 retinopathy, exhibit impaired photoreceptor ion homeostasis and slow rod degeneration, providing an opportunity to investigate metabolic adaptation during progressive dysfunction. Untargeted metabolomic profiling was performed on retinas from wildtype (WT) and Kv8.2 KO mice at 1 and 13 months of age. Principal component analysis revealed distinct profiles for aged Kv8.2 KO retinas compared with aged WT and young groups, while young WT and KO retinas were metabolically similar. The major changes in aged Kv8.2 KO retinas compared to aged WT were reduced nucleobases and nucleosides while the amino acids homocysteine, methionine, and serine were elevated. These are signature metabolites in one-carbon metabolism, a metabolic hub influencing nucleotide metabolism, epigenic regulation, and anti-oxidant defense. Supervised modeling showed that these one-carbon-related changes emerge early and progress with age in Kv8.2 KO retinas. Together, these findings implicate altered one-carbon metabolism as a key mechanism in photoreceptor vulnerability and adaptation in slow retinal degeneration.

  PublisherDOI

• Photoreceptor Ion Channels in Signaling and Disease

  Advances in experimental medicine and biology · 2023-01-01 · 4 citations

  articleSenior author
  PublisherDOI

• Mouse all-cone retina models of Cav1.4 synaptopathy

  Frontiers in Molecular Neuroscience · 2023-04-27 · 1 citations

  articleOpen accessSenior authorCorresponding

  The voltage-gated calcium channel, Cav1.4 is localized to photoreceptor ribbon synapses and functions both in molecular organization of the synapse and in regulating release of synaptic vesicles. Mutations in Cav1.4 subunits typically present as either incomplete congenital stationary night blindness or a progressive cone-rod dystrophy in humans. We developed a cone-rich mammalian model system to further study how different Cav1.4 mutations affect cones. RPE65 R91W KI; Nrl KO "Conefull" mice were crossed to Cav1.4 α1F or α2δ4 KO mice to generate the "Conefull:α1F KO" and "Conefull:α2δ4 KO" lines. Animals were assessed using a visually guided water maze, electroretinogram (ERG), optical coherence tomography (OCT), and histology. Mice of both sexes and up to six-months of age were used. Conefull: α1F KO mice could not navigate the visually guided water maze, had no b-wave in the ERG, and the developing all-cone outer nuclear layer reorganized into rosettes at the time of eye opening with degeneration progressing to 30% loss by 2-months of age. In comparison, the Conefull: α2δ4 KO mice successfully navigated the visually guided water maze, had a reduced amplitude b-wave ERG, and the development of the all-cone outer nuclear layer appeared normal although progressive degeneration with 10% loss by 2-months of age was observed. In summary, new disease models for studying congenital synaptic diseases due to loss of Cav1.4 function have been created.

  PublisherOA PDFDOI

• A visually guided swim assay for mouse models of human retinal disease recapitulates the multi-luminance mobility test in humans

  Saudi Journal of Ophthalmology · 2023-10-01 · 4 citations

  articleOpen access

  Abstract PURPOSE: The purpose of this study was to develop a visually guided swim assay (VGSA) for measuring vision in mouse retinal disease models comparable to the multi-luminance mobility test (MLMT) utilized in human clinical trials. METHODS: Three mouse retinal disease models were studied: Bardet–Biedl syndrome type 1 ( Bbs1M390R/M390R ), n = 5; Bardet–Biedl syndrome type 10 ( Bbs10−/− ), n = 11; and X linked retinoschisis (retinoschisin knockout; Rs1- KO), n = 5. Controls were normally-sighted mice, n = 10. Eyeless Pax6Sey-Dey mice, n = 4, were used to determine the performance of animals without vision in VGSA. RESULTS: Eyeless Pax6Sey-Dey mice had a VGSA time-to-platform (TTP) 7X longer than normally-sighted controls ( P < 0.0001). Controls demonstrated no difference in their TTP in both lighting conditions; the same was true for Pax6Sey-Dey . At 4–6 M, Rs1- KO and Bbs10−/− had longer TTP in the dark than controls ( P = 0.0156 and P = 1.23 × 10 −8 , respectively). At 9–11 M, both BBS models had longer TTP than controls in light and dark with times similar to Pax6Sey-Dey ( P < 0.0001), demonstrating progressive vision loss in BBS models, but not in controls nor in Rs1- KO. At 1 M, Bbs10−/− ERG light-adapted (cone) amplitudes were nonrecordable, resulting in a floor effect. VGSA did not reach a floor until 9–11 M. ERG combined rod/cone b-wave amplitudes were nonrecordable in all three mutant groups at 9–11 M, but VGSA still showed differences in visual function. ERG values correlate non-linearly with VGSA, and VGSA measured the continual decline of vision. CONCLUSION: ERG is no longer a useful endpoint once the nonrecordable level is reached. VGSA differentiates between different levels of vision, different ages, and different disease models even after ERG is nonrecordable, similar to the MLMT in humans.

  PublisherDOI

• AAV2/4-RS1 gene therapy in the retinoschisin knockout mouse model of X-linked retinoschisis

  PLoS ONE · 2022-12-07 · 13 citations

  articleOpen access

  OBJECTIVE: To evaluate efficacy of a novel adeno-associated virus (AAV) vector, AAV2/4-RS1, for retinal rescue in the retinoschisin knockout (Rs1-KO) mouse model of X-linked retinoschisis (XLRS). Brinzolamide (Azopt®), a carbonic anhydrase inhibitor, was tested for its ability to potentiate the effects of AAV2/4-RS1. METHODS: AAV2/4-RS1 with a cytomegalovirus (CMV) promoter (2x1012 viral genomes/mL) was delivered to Rs1-KO mice via intravitreal (N = 5; 1μL) or subretinal (N = 21; 2μL) injections at postnatal day 60-90. Eleven mice treated with subretinal therapy also received topical Azopt® twice a day. Serial full field electroretinography (ERG) was performed starting at day 50-60 post-injection. Mice were evaluated using a visually guided swim assay (VGSA) in light and dark conditions. The experimental groups were compared to untreated Rs1-KO (N = 11), wild-type (N = 12), and Rs1-KO mice receiving only Azopt® (N = 5). Immunofluorescence staining was performed to assess RS1 protein expression following treatment. RESULTS: The ERG b/a ratio was significantly higher in the subretinal plus Azopt® (p<0.0001), subretinal without Azopt® (p = 0.0002), and intravitreal (p = 0.01) treated eyes compared to untreated eyes. There was a highly significant subretinal treatment effect on ERG amplitudes collectively at 7-9 months post-injection (p = 0.0003). Cones showed more effect than rods. The subretinal group showed improved time to platform in the dark VGSA compared to untreated mice (p<0.0001). RS1 protein expression was detected in the outer retina in subretinal treated mice and in the inner retina in intravitreal treated mice. CONCLUSIONS: AAV2/4-RS1 shows promise for improving retinal phenotype in the Rs1-KO mouse model. Subretinal delivery was superior to intravitreal. Topical brinzolamide did not improve efficacy. AAV2/4-RS1 may be considered as a potential treatment for XLRS patients.

  PublisherOA PDFDOI

• Identification of HCN1 as a 14-3-3 client

  PLoS ONE · 2022-06-09 · 3 citations

  articleOpen accessSenior authorCorresponding

  Hyperpolarization activated cyclic nucleotide-gated channel 1 (HCN1) is expressed throughout the nervous system and is critical for regulating neuronal excitability, with mutations being associated with multiple forms of epilepsy. Adaptive modulation of HCN1 has been observed, as has pathogenic dysregulation. While the mechanisms underlying this modulation remain incompletely understood, regulation of HCN1 has been shown to include phosphorylation. A candidate phosphorylation-dependent regulator of HCN1 channels is 14-3-3. We used bioinformatics to identify three potential 14-3-3 binding sites in HCN1. We confirmed that 14-3-3 could pull down HCN1 from multiple tissue sources and used HEK293 cells to detail the interaction. Two sites in the intrinsically disordered C-terminus of HCN1 were necessary and sufficient for a phosphorylation-dependent interaction with 14-3-3. The same region of HCN1 containing the 14-3-3 binding peptides is required for phosphorylation-independent protein degradation. We propose a model in which phosphorylation of mouse S810 and S867 (human S789 and S846) recruits 14-3-3 to inhibit a yet unidentified factor signaling for protein degradation, thus increasing the half-life of HCN1.

  PublisherOA PDFDOI

• Pentameric assembly of the Kv2.1 tetramerization domain

  Acta Crystallographica Section D Structural Biology · 2022-05-30 · 4 citations

  articleOpen accessSenior author

  The Kv family of voltage-gated potassium channels regulate neuronal excitability. The biophysical characteristics of Kv channels can be matched to the needs of different neurons by forming homotetrameric or heterotetrameric channels within one of four subfamilies. The cytoplasmic tetramerization (T1) domain plays a major role in dictating the compatibility of different Kv subunits. The only Kv subfamily lacking a representative structure of the T1 domain is the Kv2 family. Here, X-ray crystallography was used to solve the structure of the human Kv2.1 T1 domain. The structure is similar to those of other T1 domains, but surprisingly formed a pentamer instead of a tetramer. In solution the Kv2.1 T1 domain also formed a pentamer, as determined by inline SEC-MALS-SAXS and negative-stain electron microscopy. The Kv2.1 T1-T1 interface involves electrostatic interactions, including a salt bridge formed by the negative charges in a previously described CDD motif, and inter-subunit coordination of zinc. It is shown that zinc binding is important for stability. In conclusion, the Kv2.1 T1 domain behaves differently from the other Kv T1 domains, which may reflect the versatility of Kv2.1, which can assemble with the regulatory KvS subunits and scaffold ER-plasma membrane contacts.

  PublisherOA PDFDOI

• Cone-Driven Retinal Responses Are Shaped by Rod But Not Cone HCN1

  Journal of Neuroscience · 2022-04-18 · 5 citations

  articleOpen accessSenior author

  Signal integration of converging neural circuits is poorly understood. One example is in the retina where the integration of rod and cone signaling is responsible for the large dynamic range of vision. The relative contribution of rods versus cones is dictated by a complex function involving background light intensity and stimulus temporal frequency. One understudied mechanism involved in coordinating rod and cone signaling onto the shared retinal circuit is the hyperpolarization activated current ( I h ) mediated by hyperpolarization-activated cyclic nucleotide-gated 1 (HCN1) channels expressed in rods and cones. I h opposes membrane hyperpolarization driven by activation of the phototransduction cascade and modulates the strength and kinetics of the photoreceptor voltage response. We examined conditional knock-out (KO) of HCN1 from mouse rods using electroretinography (ERG). In the absence of HCN1, rod responses are prolonged in dim light which altered the response to slow modulation of light intensity both at the level of retinal signaling and behavior. Under brighter intensities, cone-driven signaling was suppressed. To our surprise, conditional KO of HCN1 from mouse cones had no effect on cone-mediated signaling. We propose that I h is dispensable in cones because of the high level of temporal control of cone phototransduction. Thus, HCN1 is required for cone-driven retinal signaling only indirectly by modulating the voltage response of rods to limit their output. SIGNIFICANCE STATEMENT Hyperpolarization gated hyperpolarization-activated cyclic nucleotide-gated 1 (HCN1) channels carry a feedback current that helps to reset light-activated photoreceptors. Using conditional HCN1 knock-out (KO) mice we show that ablating HCN1 from rods allows rods to signal in bright light when they are normally shut down. Instead of enhancing vision this results in suppressing cone signaling. Conversely, ablating HCN1 from cones was of no consequence. This work provides novel insights into the integration of rod and cone signaling in the retina and challenges our assumptions about the role of HCN1 in cones.

  PublisherOA PDFDOI

• Differential impact of Kv8.2 loss on rod and cone signaling and degeneration

  Human Molecular Genetics · 2021-10-12 · 22 citations

  articleOpen accessSenior authorCorresponding

  Heteromeric Kv2.1/Kv8.2 channels are voltage-gated potassium channels localized to the photoreceptor inner segment. They carry IKx, which is largely responsible for setting the photoreceptor resting membrane potential. Mutations in Kv8.2 result in childhood-onset cone dystrophy with supernormal rod response (CDSRR). We generated a Kv8.2 knockout (KO) mouse and examined retinal signaling and photoreceptor degeneration to gain deeper insight into the complex phenotypes of this disease. Using electroretinograms, we show that there were delayed or reduced signaling from rods depending on the intensity of the light stimulus, consistent with reduced capacity for light-evoked changes in membrane potential. The delayed response was not seen ex vivo where extracellular potassium levels were controlled by the perfusion buffer, so we propose the in vivo alteration is influenced by genotype-associated ionic imbalance. We observed mild retinal degeneration. Signaling from cones was reduced but there was no loss of cone density. Loss of Kv8.2 altered responses to flickering light with responses attenuated at high frequencies and altered in shape at low frequencies. The Kv8.2 KO line on an all-cone retina background had reduced cone-driven ERG b wave amplitudes and underwent degeneration. Altogether, we provide insight into how a deficit in the dark current affects the health and function of photoreceptors.

  PublisherOA PDFDOI

• Pentameric assembly of the Kv2.1 tetramerization domain

  bioRxiv (Cold Spring Harbor Laboratory) · 2021-11-09

  preprintOpen accessSenior authorCorresponding

  Abstract The Kv family of voltage-gated potassium channels regulate neuronal excitability. The biophysical characteristic of Kv channels can be matched to the needs of different neurons by forming homotetrameric or heterotetrameric channels within one of four subfamilies. The cytoplasmic tetramerization (T1) domain plays a major role in dictating the compatibility of different Kv subunits. The only Kv subfamily missing a representative structure of the T1 domain is the Kv2 family. We used X-ray crystallography to solve the structure of the human Kv2.1 T1 domain. The structure is similar to other T1 domains but surprisingly formed a pentamer instead of a tetramer. In solution the Kv2.1 T1 domain also formed a pentamer as determined with in-line SEC-MALS-SAXS and negative stain EM. The Kv2.1 T1-T1 interface involves electrostatic interactions including a salt bridge formed by the negative charges in a previously described CDD motif, and inter-subunit coordination of zinc. We show that zinc binding is important for stability. In conclusion, the Kv2.1 T1 domain behaves differently from the other Kv T1 domains which may reflect the versatility of Kv2.1, the only Kv subfamily that can assemble with the regulatory KvS subunits and scaffold ER-plasma membrane contacts.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R21EY027054

  NIH · $419k · 2018

• Calcium channels in retinal photoreceptors

  NIH · $4.4M · 2017–2026

• Protein Targeting in Vertebrate Photoreceptors

  NIH · $3.7M · 2010–2023

Frequent coauthors

• Vadim Y. Arshavsky

  Duke University

  41 shared

• Joseph G. Laird

  University of Iowa

  20 shared

• Sidney M. Gospe

  17 shared

• Colten K. Lankford

  University of Iowa

  12 shared

• Nikolai P. Skiba

  Duke University

  11 shared

• Joseph C. Besharse

  Medical College of Wisconsin

  11 shared

• Peter J. Yoo

  Duke University

  11 shared

• Amy Lee

  The University of Texas at Austin

  9 shared

Labs

• Sarah C. W. BakerPI

Education

• Research Associate, Ophthalmology

  Duke Univ

  2009

• Postdoc, Ophthalmology

  Massachusetts Eye and Ear Infirmary

  2005

• PhD, Cell Biology, Neurobiology, and Anatomy

  Medical College of Wisconsin

  2003