Ramakrishnan Lab

black and orange inflammation imageThe laboratory of Vijay Ramakrishnan, MD at Indiana University School of Medicine focuses on airway inflammation in chronic rhinosinusitis. Ramakrishnan received his MD from Baylor College of Medicine and completed a residency in Otolaryngology at the University of Colorado. After Rhinology Fellowship at the University of Pennsylvania, he worked as Otolaryngology faculty at the University of Colorado for twelve years, as a surgeon-scientist in the Rhinology Division. While maintaining a busy clinical practice building the Endoscopic Skull Base Program, he completed a NIH K23 award in nasal chemosensation for additional translational research training. He then moved to IU School of Medicine in January 2022 as Professor of Otolaryngology—Head and Neck Surgery and Director of Rhinology Research. Dr. Ramakrishnan is also an Affiliate Scientist in Health Services Research at Regenstreif Institute, Inc, and member of the Stark Neurosciences Research institute.

Active Research

Dr. Ramakrishnan’s research interests revolve around upper airway inflammation. His basic science laboratory interests focus on dynamics of the sinus microbiome in chronic rhinosinusitis, detection and clearance of airborne irritants, and inflammation that results from these processes. As a surgeon-scientist, a high degree of translation is maintained, with ongoing projects centered on surgical outcomes, novel diagnostic tools, and personalized medicine approaches to chronic sinus disease.

Submerged Cell Culture

CRS primary epithelial cells grown at air-liquid interface. 

  • Microbiome of the sinuses (NIH R01Al175239)
    The Ramakrishnan Lab has been interested in the contributions of the microbiome to chronic mucosal inflammation in CRS. In early collaborative studies with the Frank Lab, we showed that healthy sinuses are not sterile and that clinical cultures are insufficient in enumeration of bacteria in disease. Using modern bacterial DNA detection techniques, we demonstrated that the local microbiome in CRS is compositionally different than that found in healthy subjects, even despite the underlying between-subject differences. Some common differences have been replicated by other labs, such as the preponderance for anaerobes in CRS, and associations of certain microbes with the healthy state. In a JACI 2015 article, we described sinonasal microbiome differences in CRS phenotypes, and identified Actinobacteria with good surgical outcomes in refractory CRS cases. Dysbiosis in the CRS microbiome may seemingly serve as a biomarker, and additional factor to endotype CRS subjects, or as a therapeutic target. We are interested in identifying functional roles for the microbiome in the healthy state, and potential causal mechanisms for induction or sustenance of chronic inflammation in CRS. This includes study of factors governing establishment of the airway microbiome, host-bacteria interactions at the airway surface, induction of inflammatory pathways, and resilience to perturbation.  
     
    		  
  • Chemosensory studies (NIH R21DC019490)
    In different investigations, the Ramakrishnan Lab also was one of the first to identify solitary chemosensory cells and taste transduction machinery in human sinonasal tissues. Research mentors at the Rocky Mountain Taste and Smell Center (Finger, Tizzano, Restrepo) described the function of such cells in rodents and established a role for their function in detection of irritants in the airway surface liquid. These “tufted” cells are elongated in shape with a microvillar tuft on the apical projection, express sweet and bitter taste receptors on their surface, utilize canonical taste transduction machinery, and are frequently innervated in rodents. Subsequently, we described the presence of such cells and taste transduction molecules in human sinonasal tissues using PCR and immunohistochemistry. Interest in extraoral taste receptors, particularly bitter taste receptors, has exploded in the past few years. Their presence, whether on cilia or localized to specialized chemosensory cells, has been documented in many organ systems and they may serve a role in varied physiologic functions. Our current research focuses on SCC development in the upper respiratory system and their response to airway irritants.
     

Lab Personnel

61167-Ramakrishnan, Vijay Vijay R. Ramakrishnan, MD

Vijay R. Ramakrishnan, MD

Professor of Otolaryngology-Head & Neck Surgery

Faculty Profile Placeholder IUSM Logo Khalid Khan, PhD, MSC

Khalid Khan, PhD, MSC

Postdoctoral Fellow in Otolaryngology-Head & Neck Surgery

Research Collaborators

Indiana University

Ben Gaston, MD; Mark Kaplan, MD; Thomas O'Connell, PhD; Santo Fortunato, PhD; Snehasis Mukhopadhyay, PhD; Michael Weiner, MD, MPH; Stark Neurosciences Research Institute investigators 

University of Colorado

Daniel Frank, PhD; Diego Restrepo, PhD; Eszter Vladar, PhD; Adult & Child Center for Outcomes Research & Delivery Science (ACCORDS)

University of Pennsylvania

Marco Tizzano, PhD; Eric Larson, PhD

Clinical Outcomes Researchers

Timothy Smith, MD, MPH (OHSU); Zachary Soler, MD (MUSC)

Current Funding

  • NIH R21-DC019490, PI: Ramakrishnan
    Solitary chemosensory cell development and function
    The purpose of this grant is to apply gene editing approaches to study solitary chemosensory cells in primary human sinonasal epithelial differentiated cell culture. We will define SCC development from pluripotent progenitor cells, and test their capacity to differentiate further into specialized cells in the rare epithelial cell lineage, such as ionocytes and neuroendocrine cells. In addition we will test responses to disease-associated putative ligands identified in the PIs K23 grant period through study of murine SCCs and human bitter taste receptors in a heterologous expression system.
  • NIH R01AI175239, Contact PI: Ramakrishnan (Multi-PI grant)
    CRS Microbiome: Multi-omic Integrative Longitudinal Experimental (CRS-MILE) Study
    Our central hypothesis is that dysbiosis in Chronic Rhinosinusitis (CRS) promotes chronic mucosal inflammation and compromises response to therapy. This hypothesis will be tested by pursuing three specific aims: 1) Evaluate the functional capacity of microbiome alterations observed in CRS using an integrative multi- `omics approach; 2) Determine the relationship between microbiome alterations and CRS disease severity and therapeutic outcomes in a longitudinal multi-institutional human intervention study; 3) Determine how CRS-associated microbes alter sinonasal mucosal core functions to drive disease chronicity, through in vitro experimentation.
  • NIH R01-MH128867, Co-Investigator; PIs: Shepherd/Prasse
    Scalable 3D molecular imaging and data analysis for cell census generation
    In this proposal, we propose to develop and apply new scalable 3D imaging and analysis methods to determine the location of glomeruli targeted by olfactory sensory neurons expressing specific olfactory receptors, the olfactory bulb connectome. This method will be scalable to other brain regions allowing systematic development of a human cell atlas key to understanding human brain function in health and disease.
  • NIH R01AG079193, Co-Investigator: Ramakrishnan
    Virus and olfactory system interactions accelerate Alzheimer’s disease pathology 
    In this multi-disciplinary proposal, we use mouse and human-based studies to test the hypothesis that viral infection of the olfactory epithelium induces microglial activation and central inflammatory processes in the olfactory pathways that directly accelerate Alzheimer pathology.

Select Recent Publications

  • 2023

    Biswas K, Ramakrishnan VR, Hollemann E, Lorenz K, Wagner Mackenzie B, Frank DN, Douglas RG, Hummel T. Bacterial communities in the nasal passage of post-viral olfactory dysfunction patients. Int Forum Allergy Rhinol. 2023 Feb 27. doi: 10.1002/alr.23149. Epub ahead of print. PMID: 36846913.

    Chapurin N, Schlosser RJ, Gutierrez J, Mace JC, Smith TL, Bodner TE, Khan S, Mulligan JK, Mattos JL, Alt JA, Ramakrishnan VR, Soler ZM. All chronic rhinosinusitis endotype clusters demonstrate improvement in patient-reported and clinical outcome measures after endoscopic sinus surgery. Int Forum Allergy Rhinol. 2023 Aug 10. doi: 10.1002/alr.23255. Epub ahead of print. PMID: 37563836.

    Hagedorn R, Tullis B, Nguyen C, Stockard R, Mace JC, Ramakrishnan VR, Beswick DM, Soler ZM, Smith TL, Alt JA, Gill AS. Does air pollutant exposure impact disease severity or outcomes in chronic rhinosinusitis? Int Forum Allergy Rhinol. 2023 Aug 9. doi: 10.1002/alr.23250. Epub ahead of print. PMID: 37555485.

    Whitcroft KL, Altundag A, Balungwe P,…Ramakrishnan VR…Hummel T. Position paper on olfactory dysfunction: 2023. Rhinology 2023;61:supplement 33.

    Robinson PZ, Frank DN, Ramakrishnan VR. Inflammation resolution and specialized pro-resolving lipid mediators in chronic rhinosinusitis. Expert Rev Clin Immunol. 2023 Jul-Dec;19(8):969-979. doi: 10.1080/1744666X.2023.2232554. Epub 2023 Jul 4. PMID: 37392068; PMCID: PMC10426389.

    Massey CJ, Asokan A, Tietbohl C, Morris M, Ramakrishnan VR. Otolaryngologist perceptions of AI-based sinus CT interpretation. Am J Otolaryngol. 2023 Sep-Oct;44(5):103932. doi: 10.1016/j.amjoto.2023.103932. Epub 2023 May 21. PMID: 37245324.

    Philpott C, Kumaresan K, Fjaeldstad AW, … Ramakrishnan VR, … Hummel T. Developing a core outcome set for clinical trials in olfactory disorders: a COMET initiative. Rhinology 2023 Aug 1;61(4):312-319. doi: 10.4193/Rhin22.116. PMID: 37243690.

    High B, Jetté ME, Li M, Ramakrishnan VR, et al. Variability in P2X receptor composition in human taste nerves: implications for treatment of chronic cough. ERJ Open Res. 2023 Apr 11;9(2):00007-2023. doi: 10.1183/23120541.00007-2023. PMID: 37057093; PMCID: PMC10086694.

    Asokan A, Massey CJ, Tietbohl C, Kroenke K, Morris M, Ramakrishnan VR. Physician Views of Artificial Intelligence in Otolaryngology and Rhinology: a Mixed Methods Study. Laryngoscope Investigative Otolaryngology 2023; accepted for publication.

  • 2022

    Psaltis AJ, Mackenzie BW, Cope EK, Ramakrishnan VR. Unravelling the role of the microbiome in chronic rhinosinusitis. J Allergy Clin Immunol. 2022 Mar 14:S0091-6749(22)00291-3. doi: 10.1016/j.jaci.2022.02.022. Epub ahead of print. PMID: 35300985.

    Frank DN, Qiu Y, Cao Y, Zhang S, Lu L, Kofonow JM, Robertson CE, Liu Y, Wang H, Levens CL, Kuhn KA, Song J, Ramakrishnan VR, Lu SL. A dysbiotic microbiome promotes head and neck squamous cell carcinoma. Oncogene. 2022 Feb;41(9):1269-1280. doi: 10.1038/s41388-021-02137-1. Epub 2022 Jan 28. PMID: 35087236; PMCID: PMC8882136.

    Diaz del Valle, Fernando; Zakrajsek, Jonathan; Min, Sung-Joon; Koff, Patricia; Bell, Harold; Kincaid, Keegan; Frank, Daniel; Ramakrishnan, Vijay; Ghosh, Moumita; Vandivier, Richard. Impact of Airline Secondhand Tobacco Smoke Exposure on Respiratory Health and Lung Function Decades after Exposure Cessation. Accepted for publication in CHEST. Published:March 06, 2022 DOI: https://doi.org/10.1016/j.chest.2022.02.049

    Terella AM, Mariner P, Cool CD, Ramakrishnan VR. Use of a novel Chinchilla skull base repair model to test a photo-initiated thiol-ene biopolymer. Int Forum Allergy Rhinol. 2022 Mar 28. doi: 10.1002/alr.23004. Epub ahead of print. PMID: 35344275.

    Gill AS, Beswick DM, Mace JC, et al. Evaluating Distance Bias in Chronic Rhinosinusitis Outcomes. JAMA Otolaryngol Head Neck Surg. Published online May 05, 2022. doi:10.1001/jamaoto.2022.0268

    Ramakrishnan VR, Larson E, Holt J, Frank DN. Infection and inflammation in chronic rhinosinusitis: Gene ontology/pathway analysis perspective. Int Forum Allergy Rhinol. 2022 Jul 13. doi: 10.1002/alr.23052. Epub ahead of print. PMID: 35829680.

    Asokan A, Mace JC, Rice JD, Smith TL, Soler ZM, Ramakrishnan VR. Sex Differences in Presentation and Surgical Outcomes From a Prospective Multicenter Chronic Rhinosinusitis Study. Otolaryngol Head Neck Surg. 2022 May 31:1945998221102810. doi: 10.1177/01945998221102810. Epub ahead of print. PMID: 35639480.

    Beswick DM, Humphries SM, Miller JE, Balkissoon CD, Khatiwada A, Vladar EK, Ramakrishnan VR, Lynch DA, Taylor-Cousar JL. Objective and patient-based measures of chronic rhinosinusitis in people with cystic fibrosis treated with highly effective modulator therapy. Int Forum Allergy Rhinol. 2022 May 20. doi: 10.1002/alr.23016. Epub ahead of print. PMID: 35595546.

    Massey CJ, Ramos L, Beswick DM, Ramakrishnan VR, Humphries SM. Clinical Validation and Extension of an Automated, Deep Learning–Based Algorithm for Quantitative Sinus CT Analysis. Am J Neuroradiol 2022;43(9):1318-1324.

    Schlosser RJ, Soler ZM, Mace J, Farrell N, Rimmer R, Alt JA, Ramakrishnan VR, Edwards TS, Smith TL. Profiles of Odorant Specific Performance in Olfactory Testing. Am J Rhinol Allergy. 2023 Jan;37(1):26-34. doi: 10.1177/19458924221124692. Epub 2022 Sep 6. PMID: 36069003.

    Pandrangi VC, Mace JC, Kim JH, Geltzeiler M, Detwiller KY, Soler ZM, Schlosser RJ, Alt JA, Ramakrishnan VR, Mattos JL, Smith TL. Work productivity and activity impairment in patients with chronic rhinosinusitis undergoing endoscopic sinus surgery-A prospective, multi-institutional study. Int Forum Allergy Rhinol. 2023 Mar;13(3):216-229. doi: 10.1002/alr.23070. Epub 2022 Aug 23. PMID: 35938699; PMCID: PMC9905326.

    Ramakrishnan VR, Larson E, Holt J, Frank DN. Infection and inflammation in chronic rhinosinusitis: Gene ontology/pathway analysis perspective. Int Forum Allergy Rhinol. 2022 Dec;12(12):1566-1569. doi: 10.1002/alr.23052. Epub 2022 Aug 16. PMID: 35829680; PMCID: PMC9712154.

    Bubak AN, Merle L, Niemeyer CS, Baxter BD, Gentile Polese A, Ramakrishnan V, Gomez J, Madrigal L, Villegas-Lanau A, Lopera F, Macklin W, Frietze S, Nagel MA, Restrepo D. Signatures for viral infection and inflammation in the proximal olfactory system in familial Alzheimer's disease. Neurobiol Aging. 2023 Mar;123:75-82. doi: 10.1016/j.neurobiolaging.2022.12.004. Epub 2022 Dec 13. PMID: 36638683; PMCID: PMC9889108.

  • 2021

    Nakayama T, Lee IT, Le W, Tsunemi Y, Borchard NA, Zarabanda D, Dholakia SS, Gall PA, Yang A, Kim D, Akutsu M, Kashiwagi T, Patel ZM, Hwang PH, Frank DN, Haruna SI, Ramakrishnan VR, Nolan GP, Jiang S, Nayak JV. Inflammatory molecular endotypes of nasal polyps derived from Caucasian and Japanese populations. J Allergy Clin Immunol. 2021 Dec 1:S0091-6749(21)01821-2. doi: 10.1016/j.jaci.2021.11.017. Epub ahead of print.

    Baxter BD, Larson ED, Merle L, Feinstein P, Polese AG, Bubak AN, Niemeyer CS, Hassell J Jr, Shepherd D, Ramakrishnan VR, Nagel MA, Restrepo D. Transcriptional profiling reveals potential involvement of microvillous TRPM5-expressing cells in viral infection of the olfactory epithelium. BMC Genomics. 2021 Mar 30;22(1):224. doi: 10.1186/s12864-021-07528-y.

    Soler ZM, Schlosser RJ, Bodner TE, Alt JA, Ramakrishnan VR, Mattos JL, Mulligan JK, Mace JC, Smith TL. Endotyping Chronic Rhinosinusitis Based on Olfactory Cleft Mucus Biomarkers. J Allergy Clin Immunol. 2021 Feb 4:S0091-6749(21)00166-4. doi: 10.1016/j.jaci.2021.01.021. Epub ahead of print.Vickery TW, Armstrong BA, Kofonow JM, Robertson CE, Kroehl ME, Reisdorph NA, Ramakrishnan VR*, Frank DN*. *co-corresponding authors. Altered tissue specialized pro-resolving mediators in chronic rhinosinusitis. Prostaglandins, Leukotrienes, and Essential Fatty Acids.

    Martinez-Perez R, Aref M, Ramakhrisnan V, Youssef AS. Combined biportal unilateral endoscopic endonasal and endoscopic anterior transmaxillary approach for resection of lesions involving the infratemporal fossa. Acta Neurochir (Wien) 2021;163(12):3439-3445

  • 2020

    Yao WC, Ramakrishnan VR, Luong AU, Citardi MJ. VISUALIZE: a 24-weeks, open-label study using nasal endoscopy video to evaluate the efficacy and safety of EDS-FLU 186 ug twice daily in adults with bilateral nasal polyps. Rhinology Online 2020(3):58-66.

  • 2011-2017

    Sokoya M, Ramakrishnan VR, Frank DN, Rakhola J, Getz A, Kingdom TT, Kofonow JM, Nguyen Q, Janoff EN. Expression of Immunoglobulin D is Increased in Chronic Rhinosinusitis. Annals Allergy Asthma 2017;119(4):317-323.

    Gitomer SA, Fountain CR, Kingdom TT, Getz AE, Sillau SH, Katial RK, Ramakrishnan VR. Clinical examination of tissue eosinophlia in patients with chronic rhinosinusitis and nasal polyposis. Otolaryngol Head Neck Surg 2016;155(1):173-8.

    Ramakrishnan VR, Hauser LJ, Feazel LM, Ir D, Robertson CE, Frank DN. Sinus microbiota varies among chronic rhinosinusitis phenotypes and predicts surgical outcome. J Allergy Clin Immunol 2015; 136(2):334-42. 

    Hauser LJ, Feazel LM, Ir D, Fang R, Wagner BD, Robertson CE, Frank DN, Ramakrishnan VR. Sinus culture poorly predicts resident microbiota. Int Forum 
    Allergy Rhinol 2015;5(1):3-9. 

    Ramakrishnan VR, Feazel LM, Gitomer SA, Ir D, Robertson CE, Frank DN. The microbiome of the middle meatus in healthy adults. PLoS ONE 2013; 8(12): e85507. 

    Barham HP, Cooper SE, Tizzano M, Kingdom TT, Finger TE, Kinnamon SC, Ramakrishnan VR. Solitary chemosensory cells and bitter taste receptor signaling in human sinonasal mucosa. Int Forum Allergy Rhinology 2013; 3(6):450-7.

    Feazel L, Robertson C, Ramakrishnan VR, Frank DN. Staphylococcus aureus and microbiome diversity in chronic rhinosinusitis. Laryngoscope 2011; 122(2):467-72.

    Mudd PA, Katial RK, Alam R, Hohensee S, Ramakrishnan V, Kingdom TT. Variations in expression of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase in nasal mucosa of aspirin-sensitive versus aspirin-tolerant patients with nasal polyposis. Ann Allergy Asthma Immunol 2011;107(4):353-9.

Complete List of Published Work

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