Mythily Srinivasan
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Targeting Neuroinflammation Using Novel Glucorticoid-Induced Leucine Zipper Analogs
Unresolved inflammation and altered immune signals contribute to the pathology of many chronic diseases. Dr. Srinivasan's research includes the design and development of immunotherapeutic peptides using motif-mediated protein-protein interactions as drug targets.
Recently, she investigated approaches to suppress neuroinflammation in Alzheimer's disease, the most common cause of dementia that is projected to affect over seven million individuals in the United States by 2025. These studies resulted from earlier observations that the blockade of T cell co-receptor CD28 by CD80 competitive antagonist peptides unregulated glucocorticoid-induced leucine zipper (GILZ)-an anti-inflammatory molecule that directly inhibits the pro-inflammatory transcription factor, nuclear factor-kappa B (NF-kB).
Adopting data from the GILZ and NF-kB interaction complex, Dr. Srinivasan developed modified analogs of the p65 binding motif of GIlZ. Efficacy studies, in collaboration with Dr. Debomoy Lahiri, Professor of Neuroscience, and Dr. Deborah Hickman of the IU School of Medicine, suggested that the novel therapeutics exhibited suppressive potential in cellular and animal models of Alzheimer's disease.
Together with the Indiana University Research and Technology Corporation, Dr. Srinivasan initiated a startup venture, Provaidya LLC, to develop the patented GILZ analogs as investigational new drugs and received phase I funding from the National Institutes of Aging.
Dr. Srinivasan's work to develop peptide therapeutics to suppress neuroinflammation is another example of how IUPUI faculty are TRANSLATING RESEARCH INTO PRACTICE.
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Item Assessment of Salivary Adipokines Resistin, Visfatin, and Ghrelin as Type 2 Diabetes Mellitus Biomarkers(Hindawi Publishing Corporation, 2018-02-01) Srinivasan, Mythily; Meadows, Melinda L.; Maxwell, Lisa; Oral Pathology, Medicine and Radiology, School of DentistryType 2 diabetes mellitus (T2DM) is emerging as a metabolic epidemic worldwide. Pathologically, dysregulation of many biological pathways precedes hyperglycemia and the clinical diagnosis of T2DM. Changing trajectories along the process of T2DM development necessitates frequent measurement of biomarkers for early identification of at-risk individuals and successful prevention. Increase in circulating inflammatory adipokines has been suggested as predictive of T2DM. Human saliva is an easily accessible biospecimen amenable for painless frequent collection and possesses nearly 50% of serum proteome. In this study, we measured the adipokines resistin, visfatin, TNF-α, and ghrelin as markers for T2DM in unstimulated whole saliva (UWS) using specific assay kits. Resistin and visfatin concentrations were significantly higher in T2DM saliva. Although the concentration of acylated or unacylated ghrelin was lower in diabetic saliva, the decrease was not significant. Since resistin and visfatin are biomarkers integral to T2DM pathology, their salivary assessments may receive clinical acceptance.Item Can Salivary Innate Immune Molecules Provide Clue on Taste Dysfunction in COVID-19?(Frontiers, 2021-10) Ermel, Aaron; Thyvalikakath, Thankam Paul; Foroud, Tatiana; Khan, Babar; Srinivasan, Mythily; Medicine, School of MedicineEmerging concerns following the severe acute respiratory syndrome coronavirus-2 (SARS-CoV2) pandemic are the long-term effects of coronavirus disease (COVID)-19. Dysgeusia in COVID-19 is supported by the abundant expression of the entry receptor, angiotensin-converting enzyme-2 (ACE2), in the oral mucosa. The invading virus perturbs the commensal biofilm and regulates the host responses that permit or suppress viral infection. We correlated the microbial recognition receptors and soluble ACE2 (sACE2) with the SARS-CoV2 measures in the saliva of COVID-19 patients. Data indicate that the toll-like receptor-4, peptidoglycan recognition protein, and sACE2 are elevated in COVID-19 saliva and correlate moderately with the viral load.Item COVID-19 and saliva: A primer for dental health care professionals(Wiley, 2020-08-23) Srinivasan, Mythily; Thyvalikakath, Thankam P.; Cook, Blaine N.; Zero, Domenick T.; Oral Pathology, Medicine and Radiology, School of DentistryTo contain the COVID‐19 pandemic, it is essential to find methods that can be used by a wide range of health care professionals to identify the virus. The less potential contagious nature of the collection process, the ease of collection and the convenience of frequent collection for real‐time monitoring makes saliva an excellent specimen for home‐based collection for epidemiological investigations. With respect to COVID‐19, the use of saliva offers the added advantages of greater sensitivity and potential for detection at an early stage of infection. However, the advantages from a diagnostic perspective also reflect the potential risk to dental professionals from saliva from infected patients. Although not validated in COVID‐19 patients, but by extension from studies of SARS‐CoV‐1 studies, it is suggested that using antimicrobial mouthrinses such as chlorhexidine, hydrogen peroxide or sodium hypochlorite solutions could reduce the viral load in saliva droplets and reduce the risk of direct transmission. Because large saliva droplets could deposit on inanimate surfaces, changing the personal protective equipment including the clinical gown, gloves, masks, protective eye wear and face shield between patients, as well as decontamination of the work surfaces in the clinic, could reduce the risk of indirect contact transmission.Item Differential profiles of soluble and cellular toll like receptor (TLR)-2 and 4 in chronic periodontitis(PLOS, 2018-12-20) AlQallaf, Hawra; Hamada, Yusuke; Blanchard, Steven; Shin, Daniel; Gregory, Richard; Srinivasan, Mythily; Periodontology, School of DentistryChronic periodontitis is a common inflammatory disease initiated by a complex microbial biofilm and mediated by the host response causing destruction of the supporting tissues of the teeth. Host recognition of pathogens is mediated by toll-like receptors (TLRs) that bind conserved molecular patterns shared by large groups of microorganisms. The oral epithelial cells respond to most periodontopathic bacteria via TLR-2 and TLR-4. In addition to the membrane-associated receptors, soluble forms of TLR-2 (sTLR-2) and TLR-4 (sTLR-4) have been identified and are thought to play a regulatory role by binding microbial ligands. sTLR-2 has been shown to arise from ectodomain shedding of the extracellular domain of the membrane receptor and sTLR-4 is thought to be an alternate spliced form. Many studies have previously reported the presence of elevated numbers of viable exfoliated epithelial cells in the saliva of patients with chronic periodontitis. The objective of this study was to investigate the potential value of salivary sTLR-2 and sTLR-4 together with the paired epithelial cell-associated TLR-2/4 mRNA as diagnostic markers for chronic periodontitis. Unstimulated whole saliva was collected after obtaining informed consent from 40 individuals with either periodontitis or gingivitis. The sTLR-2 and sTLR4 in saliva was measured by enzyme-linked immunosorbent assay. The TLR-2 and TLR-4 transcript in the epithelial cells in saliva was measured by real time polymerase chain reaction. While levels of sTLR-2 exhibited an inverse correlation, sTLR-4 positively correlated with clinical parameters in the gingivitis cohort. Interestingly, both correlations were lost in the periodontitis cohort indicating a dysregulated host response. On the other hand, while the sTLR-2 and the paired epithelial cell associated TLR-2 mRNA exhibited a direct correlation (r2 = 0.62), that of sTLR4 and TLR-4 mRNA exhibited an inverse correlation (r2 = 0.53) in the periodontitis cohort. Collectively, assessments of salivary sTLR2 and sTLR4 together with the respective transcripts in the epithelial cells could provide clinically relevant markers of disease progression from gingivitis to periodontitis.Item Differential profiles of soluble and cellular toll like receptor (TLR)-2 and 4 in chronic periodontitis(PLOS, 2018-12-20) AlQallaf, Hawra; Hamada, Yusuke; Blanchard, Steven; Shin, Daniel; Gregory, Richard; Srinivasan, Mythily; Periodontology, School of DentistryChronic periodontitis is a common inflammatory disease initiated by a complex microbial biofilm and mediated by the host response causing destruction of the supporting tissues of the teeth. Host recognition of pathogens is mediated by toll-like receptors (TLRs) that bind conserved molecular patterns shared by large groups of microorganisms. The oral epithelial cells respond to most periodontopathic bacteria via TLR-2 and TLR-4. In addition to the membrane-associated receptors, soluble forms of TLR-2 (sTLR-2) and TLR-4 (sTLR-4) have been identified and are thought to play a regulatory role by binding microbial ligands. sTLR-2 has been shown to arise from ectodomain shedding of the extracellular domain of the membrane receptor and sTLR-4 is thought to be an alternate spliced form. Many studies have previously reported the presence of elevated numbers of viable exfoliated epithelial cells in the saliva of patients with chronic periodontitis. The objective of this study was to investigate the potential value of salivary sTLR-2 and sTLR-4 together with the paired epithelial cell-associated TLR-2/4 mRNA as diagnostic markers for chronic periodontitis. Unstimulated whole saliva was collected after obtaining informed consent from 40 individuals with either periodontitis or gingivitis. The sTLR-2 and sTLR4 in saliva was measured by enzyme-linked immunosorbent assay. The TLR-2 and TLR-4 transcript in the epithelial cells in saliva was measured by real time polymerase chain reaction. While levels of sTLR-2 exhibited an inverse correlation, sTLR-4 positively correlated with clinical parameters in the gingivitis cohort. Interestingly, both correlations were lost in the periodontitis cohort indicating a dysregulated host response. On the other hand, while the sTLR-2 and the paired epithelial cell associated TLR-2 mRNA exhibited a direct correlation (r2 = 0.62), that of sTLR4 and TLR-4 mRNA exhibited an inverse correlation (r2 = 0.53) in the periodontitis cohort. Collectively, assessments of salivary sTLR2 and sTLR4 together with the respective transcripts in the epithelial cells could provide clinically relevant markers of disease progression from gingivitis to periodontitis.Item Distinct Salivary Biomarker Profile in Chronic Periodontitis(Office of the Vice Chancellor for Research, 2012-04-13) Prakasam, S.; Srinivasan, MythilyBackground: Saliva has potential to diagnose chronic periodontitis (CP). Changes in tissue-expression of pattern-recognition-receptors (PRRs), which recognize periodontal-pathogens, correlate with CP. It follows that PRRs-expression in nucleated-cells (NCs) shed in saliva and soluble-PRRs may differentiate CP from health. Additionally, cytokines in gingival cervical fluid (GCF) correlate with worsening CP, which may be reflected in saliva. One significant test for biomarkers is changes in response to treatment. Objectives: Comparison of CP salivary-biomarkers profile with health and to study treatment effects of scaling and root planning (SRP). Methods: Unstimulated whole saliva (UWS) collection and recording of routine clinical periodontal parameters was done for two groups (n=16): healthy (H) (minimal clinical loss of attachment (CAL) and clinical inflammation) and CP (≥30% sites with ≥4mm CAL). UWS was collected at 3 different time points: before, 1-week and 6-weeks after SRP from the CP group. NCs and clarified saliva (CS) were separated from UWS. Messenger RNA was extracted from NCs and TLR-2 expression was quantitated through real-time-PCR. CS depleted of immunoglobulin and amylase to prevent large molecule interferences and diluted to 1 μg/ml of salivary-protein in PBS, normalize for variations in liquid volume, was used to quantify biomarkers through ELISA. Statistical significance between H- and CP-groups biomarkers was determined through Mann-Whitney ‘U' test and one tailed paired ‘t' test. Results: Statistically significant differences were noted for clinical profiles of H- and CP-groups and for changes after SRP within CP-group. Salivary sTLR-2, IL-17 and IL-10, were significantly higher, and sCD14, IL-6, IL-4 and TLR-2 mRNA were significantly lower in H compared to CP. In CP, salivary sTLR-2 and IL10 increased significantly at 1- and 6-weeks after SRP, whilst IL-4 decreased significantly at 6-weeks. Conclusions: Salivary biomarkers profiles are distinct between health and CP as well as before and after SRP treatment. sTLR-2, IL-10 and IL-4 may serve as short-term biomarkers for monitoring response to SRP. sCD14, TLR2-mRNA and other cytokines need exploration as long-term response biomarkers. Depletion of amylase and immunoglobulin, and normalization for total salivary protein may be important in biomarkers quantification.Item Enhancement of Cancer Immunotherapy Using Immune Modulating Peptides(Office of the Vice Chancellor for Research, 2013-04-05) Chang, Hua-Chen; Han, Ling; Lewis, David; Tung, Chun-Yu; Srinivasan, Mythily; Robertson, Michael J.; Yeh, Wu-KuangImmune Peptide Therapeutics (IPT) LLC, an Indiana-based small business and its research partner Indiana University previously identified a novel property of lunasin as a distinct class of immune modulating agent that enhances anti-tumor immunity, which may promote disease-free survival by limiting tumor progression, and thus prolong lives of cancer patients. Lunasin, a synthetic 43-amino acid peptide, was originally isolated from soybeans. Our studies have demonstrated that lunasin exerts robust synergistic effects with cytokines on augmenting IFNγ and granzyme B expression by Natural Killer (NK) cells, which is associated with increased tumoricidal activity of NK cells. In addition, this combination regimen is capable of rescuing IFNγ production ex vivo by NK cells from chemotherapy-treated Non-Hodgkin’s Lymphoma (NHL) patients who are immunocompromised with acquired immune deficiency. The long-term goal is to develop an efficacious immunotherapy which will impact the treatment and improve the clinical outcomes for NHL patients. The dose-response study indicates the optimum concentration of lunasin is at the range of μM, which would undermine its use in clinical studies. To enhance the medicinal value lunasin must be optimized for in vitro and in vivo efficacy. The objective is to develop a second generation of lunasin, which will increase its potency to improve the performance. In this study we have implemented several strategies to design and modify the prototype. The newly developed peptide called IPT.103 has 15 amino acids that are in the D-isoform configuration. Activity of IPT.103 has been tested in vitro with EC50 of 0.78 μM as compared to 4.54 μM for lunasin. IPT.103 also has in vivo activity on enhancing the serum levels of IFNγ production using a mouse model. Taken together, we have developed a peptide derivative (IPT.103) that deviates from its parental type lunasin to increase intellectual merit for commercialization as well as support clinical application.Item Epithelial expression of keratinocytes growth factor in oral precancer lesions(2016) Jimson, Sudha; Murali, S.; Zunt, Susan L.; Goldblatt, Lawrence I.; Srinivasan, Mythily; Department of Oral Pathology, Medicine and Radiology, School of DentistryBackground: Keratinocyte growth factor (KGF) is a potent epithelial mitogen that acts by binding the KGF receptors (KGFRs) expressed on epithelial cells and regulates proliferation and differentiation. The objective of this study was to investigate the expression of KGF in the epithelium in oral precancer. Materials and Methods: Archival tissues of oral submucous fibrosis (SMF) and leukoplakia were assessed for epithelial KGF expression by immunohistochemistry and real-time quantitative polymerase chain reaction. Results: KGF was predominantly expressed in the basal and parabasal cells in the epithelium of SMF tissues. KGF transcript in the epithelial cells increased with increasing severity of epithelial dysplasia in oral leukoplakia. Conclusion: Although widely reported as a product secreted by the mesenchymal cells, our data suggest that the KGF is also expressed in oral epithelial cells much like the expression in ovarian epithelial cells. Based on the localization of KGF in cells at the epithelial mesenchymal junction and that of the reported presence of KGFR in oral keratinocytes, a potential mechanism involving paracrine and autocrine interactions of KGF and KGFR in early stages of oral precancer is postulated.Item Functional characterization of a competitive peptide antagonist of p65 in human macrophage- like cells suggests therapeutic potential for chronic inflammation(2014-12) Srinivasan, Mythily; Blackburn, Corinne; Lahiri, DebomoyGlucocorticoid-induced leucine zipper (GILZ) is a glucocorticoid responsive protein that links the nuclear factor-kappa B (NFκB) and the glucocorticoid signaling pathways. Functional and binding studies suggest that the proline-rich region at the carboxy terminus of GILZ binds the p65 subunit of NFκB and suppresses the immunoinflammatory response. A widely-used strategy in the discovery of peptide drugs involves exploitation of the complementary surfaces of naturally occurring binding partners. Previously, we observed that a synthetic peptide (GILZ-P) derived from the proline-rich region of GILZ bound activated p65 and ameliorated experimental encephalomyelitis. Here we characterize the secondary structure of GILZ-P by circular dichroic analysis. GILZ-P adopts an extended polyproline type II helical conformation consistent with the structural conformation commonly observed in interfaces of transient intermolecular interactions. To determine the potential application of GILZ-P in humans, we evaluated the toxicity and efficacy of the peptide drug in mature human macrophage-like THP-1 cells. Treatment with GILZ-P at a wide range of concentrations commonly used for peptide drugs was nontoxic as determined by cell viability and apoptosis assays. Functionally, GILZ-P suppressed proliferation and glutamate secretion by activated macrophages by inhibiting nuclear translocation of p65. Collectively, our data suggest that the GILZ-P has therapeutic potential in chronic CNS diseases where persistent inflammation leads to neurodegeneration such as multiple sclerosis and Alzheimer’s disease.Item Functional characterization of a competitive peptide antagonist of p65 in human macrophage-like cells suggests therapeutic potential for chronic inflammation(Dove Medical Press, 2014) Srinivasan, Mythily; Blackburn, Corinne; Lahiri, Debomoy K.; Department of Oral Pathology, Medicine and Radiology, IU School of DentistryGlucocorticoid-induced leucine zipper (GILZ) is a glucocorticoid responsive protein that links the nuclear factor-kappa B (NFκB) and the glucocorticoid signaling pathways. Functional and binding studies suggest that the proline-rich region at the carboxy terminus of GILZ binds the p65 subunit of NFκB and suppresses the immunoinflammatory response. A widely-used strategy in the discovery of peptide drugs involves exploitation of the complementary surfaces of naturally occurring binding partners. Previously, we observed that a synthetic peptide (GILZ-P) derived from the proline-rich region of GILZ bound activated p65 and ameliorated experimental encephalomyelitis. Here we characterize the secondary structure of GILZ-P by circular dichroic analysis. GILZ-P adopts an extended polyproline type II helical conformation consistent with the structural conformation commonly observed in interfaces of transient intermolecular interactions. To determine the potential application of GILZ-P in humans, we evaluated the toxicity and efficacy of the peptide drug in mature human macrophage-like THP-1 cells. Treatment with GILZ-P at a wide range of concentrations commonly used for peptide drugs was nontoxic as determined by cell viability and apoptosis assays. Functionally, GILZ-P suppressed proliferation and glutamate secretion by activated macrophages by inhibiting nuclear translocation of p65. Collectively, our data suggest that the GILZ-P has therapeutic potential in chronic CNS diseases where persistent inflammation leads to neurodegeneration such as multiple sclerosis and Alzheimer's disease.
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