Visvanathan Ramamurthy, PhD

Research Interests

Protein Diversity in Sensory Systems: From Mechanism to Therapy

Our laboratory studies how protein diversity shapes the development and function of sensory tissues, how disruption of these molecular systems causes vision and hearing disorders, and how mechanistic discoveries can guide the development of new therapies.

Cells generate many related protein forms, or proteoforms, through the expression of different members of a protein family, alternative RNA processing, and post-translational modifications. While these proteins may share similarities, they are not always interchangeable. Even minor differences in their sequence, structure, modifications, localization, or interaction partners can determine whether a protein can fulfill a specific function in a given cell or tissue. Our research explores how this molecular diversity contributes to the biology of the retina and middle ear.

Protein diversity and specialized cellular function

Sensory tissues contain highly specialized cells and cellular structures that place unusual demands on their proteins. We study why particular forms of molecular chaperones, cytoskeletal proteins, and other protein families are uniquely required in these systems.

In the retina, we focus on photoreceptors, the light-sensing neurons that enable vision. Rod and cone photoreceptors perform related functions but differ in their protein composition, metabolism, structure, and susceptibility to disease. We investigate why closely related proteins can have distinct roles in these cells and how protein folding, assembly, modification, trafficking, and quality control support photoreceptor development and function.

Our middle-ear research examines the same broad question of protein diversity by studying motile cilia. These microscopic structures move fluid and help maintain a healthy middle-ear environment. Motile cilia are built from microtubules containing several closely related forms of tubulin, yet these forms are not always functionally equivalent. We study why a particular β-tubulin, TUBB4B, is uniquely required for normal cilia formation and function, why other tubulins cannot fully replace it, and how loss of this specialization leads to chronic middle-ear disease and hearing loss.

Together, these projects address a fundamental biochemical question: how do small molecular differences among related proteins give rise to specialized cellular functions?

How neighboring cells shape photoreceptor development and function

Photoreceptors do not develop or function in isolation. Their outer segments, the specialized structures that capture light, are formed and maintained through close interactions with neighboring support cells.

We are particularly interested in how the retinal pigment epithelium and Müller glial cells influence outer-segment development, organization, metabolism, renewal, and survival. These neighboring cells provide nutrients, remove waste, make direct physical contact with photoreceptors, and communicate through cellular extensions and secreted signals.

Our work asks how these external influences help photoreceptors build and maintain functional outer segments and how disruption of the photoreceptor–support cell interface contributes to retinal degeneration.

This approach expands the study of inherited blindness beyond defects within the photoreceptor itself, considering how the surrounding cellular environment can influence disease progression and therapeutic response.

Disease modeling and therapeutic development

We investigate inherited retinal diseases, including severe forms of childhood blindness. Our goal is to understand how disease-causing mutations alter protein function, cellular pathways, photoreceptor development, and interactions with neighboring tissues.

We use genetically engineered animal models, patient-derived induced pluripotent stem cells, and three-dimensional retinal organoids that reproduce important features of developing human retinal tissue. These complementary models allow us to connect molecular defects to changes in cellular function, tissue development, and disease progression.

Our laboratory combines protein biochemistry, molecular and cell biology, proteomics, gene editing, microscopy, metabolic analysis, and functional testing. By integrating these approaches, we can examine disease across multiple levels, from individual proteins and protein networks to intact tissues and human cellular models.

A major translational goal of the laboratory is to develop treatments that provide durable preservation or restoration of vision. Gene therapy can correct an underlying genetic defect, but it may not fully rescue photoreceptors that are already stressed, damaged, or developing in an abnormal cellular environment. We are therefore developing combination therapies that pair gene correction with additional interventions designed to protect photoreceptors, improve metabolism, reduce cellular stress, and strengthen support from neighboring tissues.

Our long-term objective is to identify the most effective therapeutic combinations and advance them toward clinical trials for children with inherited blindness.

Research training and opportunities

Students and fellows in the laboratory can receive training in protein biochemistry, molecular and cell biology, microscopy, proteomics, gene editing, animal models, cilia biology, patient-derived stem cells, retinal organoids, gene therapy, and preclinical therapeutic testing.

Projects range from fundamental studies of protein diversity and cell–cell interactions to human disease modeling and the development of new treatments for sensory disorders. Previous experience in vision or hearing research is not required.

Grants and Research

        This project will investigate how RNA binding proteins boost protein expression in photoreceptor cells to enable vision, an unexplored aspect of the photoreceptor cell biology. Our work will allow us to better understand how photoreceptors function and how blinding disease develops. We expect that the results of this study will open new ways to treat blinding diseases

HRSA – Congressionally Directed Spending (CDS)

Co-PI (or POC), Visual Impairment and intervention Strategies, $1,160,000.00

Helps to purchase a mass-spec and TEM.

Collaborators: Karen Martin, Peter Perotta and Jianhai Du.

Publications

[2026]

• Aliff HL, Crockett AB, Munezero D, Reid C, Bockius HG, Kuzak SG, Rhodes S, Saravanan T, Ramamurthy V. Cytosolic heat shock protein 90 is required for photoreceptor outer segment development and vision. J Biol Chem. 2026 Jul;302(7):113192. doi: 10.1016/j.jbc.2026.113192. Epub 2026 May 24. PMID: 42184858; PMCID: PMC13315092.

[2025]

• Kolandaivelu S, Saravanan T, Ramamurthy V. Postprenylation processing of phosphodiesterase is critical for robust cone photoreceptor response. Sci Rep. 2025 Oct 21;15(1):36646. doi: 10.1038/s41598-025-20477-w. PMID: 41120552; PMCID: PMC12541050.

• Hoda J, Aliff HL, Deng WT, Ramamurthy V. HSP90α is specifically required for rod photoreceptor function and cannot be replaced by HSP90β. bioRxiv 2025.06.05.657739; doi: https://doi.org/10.1101/2025.06.05.657739 
  • Also check the Science Cast summary of the work: https://sciencecast.org/casts/gi49wtdb13p8
• Aliff HL, Crockett AB, Chrenek MA, Nickerson JM, Boatright JH, Tseytlin O, Johnson M, Bockius HG, Kuzak SG, Ramamurthy V. Accessible LED Lightbox for Light-induced Retinal Damage in Pigmented Mice. Invest Ophthalmol Vis Sci. 2025 Feb 3;66(2):49. doi: 10.1167/iovs.66.2.49. PMID: 39969479; PMCID: PMC11841687.

[2024]

• Sanzhaeva U, Boyd-Pratt H, Bender PTR, Saravanan T, Rhodes SB, Guan T, Billington N, Boye SE, Cunningham CL, Anderson CT, Ramamurthy V. TUBB4B is essential for the cytoskeletal architecture of cochlear supporting cells and motile cilia development. Commun Biol. 2024 Sep 14;7(1):1146. doi: 10.1038/s42003-024-06867-2. PMID: 39277687; PMCID: PMC11401917.
• Sanzhaeva U, Wonsettler NR, Rhodes SB, Ramamurthy V. TUBB4B is essential for the expansion of differentiating spermatogonia. Sci Rep. 2024 Sep 7;14(1):20889. doi: 10.1038/s41598-024-71303-8. PMID: 39244620; PMCID: PMC11380678.
• Yanardag S, Rhodes S, Saravanan T, Guan T, Ramamurthy V. Prominin 1 is crucial for the early development of photoreceptor outer segments. Sci Rep. 2024 May 7;14(1):10498. doi: 10.1038/s41598-024-60989-5. PMID: 38714794; PMCID: PMC11076519.
• Aljammal R, Saravanan T, Guan T, Rhodes S, Robichaux MA, Ramamurthy V. Excessive tubulin glutamylation leads to progressive cone-rod dystrophy and loss of outer segment integrity. Hum Mol Genet. 2024 Apr 18;33(9):802-817. doi: 10.1093/hmg/ddae013. PMID: 38297980; PMCID: PMC12099296.

[2023]
 

• Munezero D, Aliff H, Salido E, Saravanan T, Sanzhaeva U, Guan T, Ramamurthy V. HSP90α is needed for the survival of rod photoreceptors and regulates the expression of rod PDE6 subunits - PubMed (nih.gov) J Biol Chem. 2023 May 10:104809. doi: 10.1016/j.jbc.2023.104809. Epub ahead of print. PMID: 37172722.
• Moakedi F, Aljammal R, Poria D, Saravanan T, Rhodes SB, Reid C, Guan T, Kefalov VJ, Ramamurthy V. Prenylation is essential for the enrichment of cone phosphodiesterase-6 (PDE6) in outer segments and efficient cone phototransduction - PubMed (nih.gov) Hum Mol Genet. 2023 Jun 29:ddad108. doi: 10.1093/hmg/ddad108. Epub ahead of print. PMID: 37384398.

[2022]

• Matalkah F, Jeong B, Sheridan M, Horstick E, Ramamurthy V, Stoilov P. The Musashi proteins direct post-transcriptional control of protein expression and alternate exon splicing in vertebrate photoreceptors - PubMed (nih.gov). Commun Biol. 2022 Sep 24;5(1):1011. doi: 10.1038/s42003-022-03990-w. PMID: 36153373; PMCID: PMC9509328.
• Matalkah F, Rhodes S, Ramamurthy V, Stoilov P. The mAB 13A4 monoclonal antibody to the mouse PROM1 protein recognizes a structural epitope - PubMed (nih.gov) PLoS One. 2022 Oct 10;17(10):e0274958. doi: 10.1371/journal.pone.0274958. PMID: 36215230; PMCID: PMC9550058.

[2020]