The laboratory of Vijay Ramakrishnan, MD at Indiana University School of Medicine focuses on airway inflammation in chronic rhinosinusitis. Dr. 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 tolaryngology 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 studying the role of nasal chemosensation in airway mucosal host-microbe interactions. He then moved to IU School of Medicine in 2022 as professor of otolaryngology—head and neck surgery and director of rhinology research. His current research program is funded by two NIH R01 grants to study the origin and persistence of chronic mucosal inflammation in chronic rhinosinusitis, and develop novel targeted approaches for its management. Through translational research including prospective studies of treatment outcomes, laboratory testing of biospecimens, qualitative studies of surgeon and patient needs, his research focuses on how to get the best results for patients with chronic rhinosinusitis and/or nasal polyps. His current NIH-funded research uses the newest technologies to study individual differences in chronic rhinosinusitis, predict responses to surgery, restore normal sinus function without antibiotics or steroids, and use AI to help patients personalize their decisions to meet their individual needs.
Dr. Ramakrishnan is also an affiliate scientist in health services research at Regenstreif Institute, Inc, and member of the Stark Neurosciences Research Institute. Collaborations with these impactful research groups ensure translation to clinical value and novel, cutting-edge approaches to studying contributions of the olfactory and trigeminal systems to health and disease.
Active Research
Dr. Ramakrishnan’s research focuses on restoring health in inflammatory disorders of the sinonasal cavity such as chronic rhinosinusitis and olfactory dysfunction. 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. 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.
Video
Submerged Cell Culture Scratch Assay
CRS primary epithelial cells grown in an injury model to test wound closure over 24hrs.
Chronic rhinosinusitis (CRS) affects ~10% of American adults and is one of the top ten most costly medical conditions in the United States. It is associated with severe but variable quality of life detriment, and our project focuses on individualizing treatment recommendations through understanding receptiveness to machine learning/artificial intelligence in clinical care, informing personalized clinical decision-making, and ultimately improving patient satisfaction.
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.
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.
The Chronic Rhinosinusitis (CRS) Problem and an AI Driven Personalized Medicine Solution
Chronic rhinosinusitis (CRS) is a highly prevalent disease that inflicts a severe quality-of-life (QOL) impairment, with local symptoms of nasal blockage, congestion, loss of smell, nasal drainage, headache, and recurrent infections. CRS is also appreciated for its prominent role as a compounding factor in other respiratory diseases such as allergic rhinitis, asthma/COPD, and cystic fibrosis. General health concerns including fatigue, sleep dysfunction, anxiety/depression, excessive medication usage, frequent physician visits, and productivity loss often accompany nasal symptoms and contribute to overall health detriment. As a result of local symptom burden and overall health disturbance, CRS has been ranked among the most severe health ailments, alongside congestive heart failure and end-stage renal disease. Among existing therapeutic options for CRS, outcomes vary widely. The stepwise approach to CRS management results in slow and measured escalation of care only after repeated attempts at various medical therapies. As nuanced understanding of disease trajectories are uncovered through deep phenotyping of individuals with CRS, a precision approach to this chronic disease is on the horizon. A patient’s decision to commit to aggressive CRS treatment, such as surgery, includes many personal factors but inherently relies on the likelihood for symptom improvement. Not surprisingly, the degree of symptom improvement gained is the primary contributor to patient satisfaction with the intervention. Though numerous risk factors have been associated with symptom severity and outcomes in CRS, there is a notable void in translation of these observations to real-world, clinical decision-making. This is due to the many possible predictor variables, unclear disease natural history, and weakness of traditional statistical approaches in dealing with noisy data. Indeed, weighing these many considerations is a complex clinical task. Our long-term goal is to create a personalized predictive model that can help individual patients understand their likely outcomes with available therapeutic options. Translating research observations into a comprehensible platform for shared decision-making, precision medicine, and rational allocation of system resources (i.e., cost-benefit analyses) would be truly innovative in CRS. Our central hypothesis is that machine learning and artificial intelligence approaches can be applied to myriad demographic and clinical data to infer clinical outcomes for individuals deciding when to pursue surgical treatment for CRS. The proposed research is significant because of its potential to: (1) illuminate how disease manifestations occur in some but not all CRS patients, (2) predict patient trajectories and inform clinical interventions, (3) support real-time clinical decision making, (4) develop new patient-centered treatment algorithms, and (5) serve as an initial study of predictive analytics informing the decision for elective surgical therapies in chronic disease.
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.
PIs Julie Liu, PhD and Jonathan Ting, MD, MS, MBA Minimally invasive endoscopic approaches to skull base surgery rely on reliably methods for dural reconstruction, where grafts may fail to adhere to dural tissues by pressures exerted by CSF or due to shear stresses experienced by the graft on the dural plane. In this study, we propose to test burst pressure and adhesive strength of a novel mussel-inspired biobased sealant to specifically address the challenge of strength in a wet environment. We will also study in vivo biocompatibility of sealant formulations in a cell culture and rodent models. Visit the Liu lab website.
PIs Yunjie Tong, PhD, and Vijay Ramakrishnan, MD This project aims to develop a novel optical imaging approach to objectively evaluate human olfactory function for improved diagnosis, prognosis, and therapeutics. We will combine near infrared spectroscopy (NIRS) technology with nasal endoscopy to create an objective clinical assessment of olfactory signal processing for clinical and research uses. Visit the Tong lab website.
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.
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 2024;14(4):765-774.
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 2024;14(4):755-764.
Whitcroft KL, Altundag A, Balungwe P,…Ramakrishnan VR…Hummel T. Position paper on olfactory dysfunction: 2023. Rhinology 2023;61:supplement 33.
Babahaji LM, Ganeshan V, Nguyen TS, Ahmed O, Barton BM, Chandra R, Chen PG, Gudis DA, Halawi A, Higgins TS, Joe SA, Kuan EC, Marino MJ, Patel ZM, Ramakrishnan VR, Rangarajan SV, Riley CA, Roxbury CR, Tabaee A, Tang DM, Wu AW, Yim MT, Bidwell J, McCoul ED. Features of Importance in Nasal Endoscopy: Deriving a Meaningful Framework. Otolaryngol Head Neck Surg. 2024 Jul 5. doi: 10.1002/ohn.889. Epub ahead of print. PMID: 38967295.
Massey CJ, Humphries SM, Mace JC, Smith TL, Soler ZM, Ramakrishnan VR. Multi-institutional validation of an AI-based sinus CT analytic platform with olfactory assessments. Int Forum Allergy Rhinol 2024 Jul 12. doi: 10.1002/alr.23410. Epub ahead of print. PMID: 38995344.
Tullis B, Mace JC, Hagedorn R, Nguyen C, Stockard R, Massey C, Ramakrishnan VR, Beswick DM, Soler ZM, Smith TL, Alt JA, Gill AS. The Impact of Acute Peri-operative Particulate Matter Exposure on Endoscopic Sinus Surgery Outcomes: A Preliminary Multi-site Investigation. Am J Rhinol Allergy. 2024;38(4):237-244.
Gill AS, Tullis B, Mace JC, Massey C, Pandrangi VC, Gutierrez JA, Ramakrishnan VR, Beswick DM, Soler ZM, Smith TL, Alt JA. Health care disparities and chronic rhinosinusitis: Does neighborhood disadvantage impact outcomes in sinonasal disease? Int Forum Allergy Rhinol. 2024 Feb 17. doi: 10.1002/alr.23337. Epub ahead of print. PMID: 38367249.
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.
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.
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.
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
