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Mast cells are a key phenotype in driving the IC/PBS disease process. LL-37 induced cystitis mimics IC/PBS with the activation and proliferation of mast cells (immunohistochemically stained red).
Our patented modified GAG therapeutic (labeled with fluorescent green tag) demonstrates both robust surface coating and deep tissue penetration in the bladder.
Robust mast cell activation (right panel, brown stained cells) observed in all tissue layers of the bladder in LL-37 induced cystitis. Control bladders (left panel) demonstrated no evidence of mast cells.
Interstitial cystitis/painful bladder syndrome (IC/PBS) is a debilitating chronic condition that affects 3.2 to 7.9 million women above the age of 18 in the US. IC/PBS causes unrelenting bladder pain, frequent urination and discomfort. Currently, there are no effective treatments for this chronic, life-altering condition.
The Oottamasathien Laboratory at Massachusetts General Hospital is focused on understanding the inflammatory cascade for better care and treatment of those suffering from IC/PBS.
The lab is exploring the disease physiologically and searching for a treatment through its proprietary murine model.
Specifically, the Oottamasathien lab is examining the antimicrobial properties of cathelicidin (LL-37) and its potential to initiate the inflammatory cascade response. The team is researching its mechanistic role in IC/PBS and discovering how to inhibit the inflammatory cascade by limiting LL-37 mediated bladder inflammation, fibrosis, and pain. In addition, the group is exploring potent anti-inflammatory and non-opioid analgesic therapeutics based on a unique and patented sulfated glycosaminoglycan (SAGE).
Siam Oottamasathien, MD, FAAP, FACS
Director of Pediatric Urology Basic Science Research, Massachusetts General Hospital for Children Division of Pediatric Urology Associate Professor of Surgery/Pediatric Urology, Harvard Medical School
Dr. Oottamasathien launched a pediatric urology basic science research program for his previous group at the University of Utah in 2007. His initial work was in the Department of Human Molecular Biology and Genetics, investigating the role of T-box proteins in genitourinary development. During that time, he gained invaluable research tools, developed elaborate experimental designs, including the use of germ-line and conditional mutagenesis experiments in mice, and further enhanced his background in genitourinary embryology, molecular biology, and developmental biology. In addition, he was awarded a three-year NIH T32 training grant (5T32HL079874) under the auspices of Nobel Laureate Dr. Mario Capecchi and received NIH loan repayment program (LRP) funding for pediatric research. After spending a year and a half along this line of research, more clinical translational science was necessary and he partnered with the laboratory of Glenn Prestwich, PhD, a senior investigator and presidential professor of medicinal chemistry at the University of Utah.
Since establishing his collaboration with Dr. Prestwich, his projects have demonstrated great potential in making a significant impact towards treating both adult and pediatric urologic disease conditions. The scientific aspects build upon novel hyaluronic acid (HA)—based biomaterials and have been used to investigate and treat bladder inflammatory, pain, and fibrotic conditions. Thus far, he has obtained grant funding from the National Kidney Foundation—Utah Chapter, Early Career Development Award from the Primary Children’s Hospital Foundation, NIH K12 Career Development Award (UL1RR025764) University of Utah Center for Clinical and Translational Science, American Urological Association/Pfizer Award for Investigation in Benign Urologic Disease, Primary Children’s Hospital Integrated Science Award, and an NIH Phase I SBIR Grant (R43DK093413) in conjunction with a small startup company GlycoMira Therapeutics that Dr. Oottamasathien is still a part of. Dr. Oottamasathien has also received NIH R01 funding to further investigate the treatment of bladder pain by novel glycosaminoglycan derivatives (R01DK100868). Dr. Oottamasathien has been a three-time recipient (2006, 2010, 2012) of the prestigious Basic Science Research Award presented by the American Academy of Pediatrics Section on Urology. He was also selected in 2013 by the Society of Pediatric Urology as their early career investigator representative and presented his group’s work at the 2013 American Urologic Association Annual Meeting showcasing the best of the best early career investigators. At this forum, he was awarded 2nd place honors. His research efforts continue to represent significant, innovative, and high-impact science that continues to move the field of urology forward.
Wanjian Jia, MD, PhD, Research Associate
Interstitial cystitis/painful bladder syndrome (IC/PBS) is a debilitating chronic condition primarily affecting women. 3.2 to 7.9 million women over the age of 18 in the US suffer from IC/PBS. With no current effective treatments IC/PBS causes unrelenting bladder pain, frequent urination, and discomfort. Extreme cases show a huge impact on quality of life with patients having to urinate over 60 times a day and seven times throughout the night. Moreover, in several recent clinical trials, various compounds failed to show any promising effectiveness against IC/PBS. The direct and indirect costs for US IC/PBS patients and their families, including increased medical expenses and decreased work productivity, is estimated to be on the order of $21.1 billion dollars annually.
Although the etiology of IC/PBS is poorly understood, a large body of literature implicates urothelial cell injury and mast cell activation as key factors in the pathogenesis of the disease. Pathologic studies have shown patient symptoms are correlated with lesions of the urothelium lining the bladder and the accumulation of mast cells throughout all layers. Contributing mechanisms include deficiencies in the glycosaminoglycan (GAG) layer of the bladder and mast cell-mediated neuro-inflammation.
The Oottamasathien laboratory has developed a mouse model of inflammatory cystitis that is physiologically relevant, biologically based, non-infectious, non-chemically induced, and recapitulates key clinical aspects of IC/PBS using the natural catheliciden (LL-37). Through this model we have shown that LL-37 induces cystitis, both acutely and chronically, with severity of inflammation being dose dependent. After a single insult of LL-37, bladders demonstrated severe inflammation with global erythema, hemorrhage, edema and hypervascularity.
Our most recent work has implicated mast cells as a key cell type in driving both inflammation and pain in our LL-37 induced bladder injury model. Our model has also yielded prolonged pain responses to be independent of acute inflammation, more closely mimicking what has been observed in patients with IC/PBS. In addition, our patented SAGE compounds have been demonstrated to substantially attenuate both inflammation and pain, and may represent a new class of non-opioid based analgesics for future therapeutic use. Finally, recent work with innovative thermosensitive biopolymers have demonstrated a more sustained delivery system of therapeutics to target organs of interest.
Further mechanistic studies are being performed to hopefully one day fully understand and elucidate the entire mechanistic role LL-37 plays in IC/PBS, both acutely and chronically. Our lab is making great headway in understanding and treating IC/PBS, bridging the gap between bench top to bedside.
Our lab is currently in search of post-doctoral MD or MD/PhD research candidates and senior research associates. Email Dr. Oottamasathien to learn more.
Amniotic therapeutic biomaterials in urology: current and future applications.
Oottamasathien S, Hotaling JM, Craig JR, Myers JB, Brant WO.
Transl Androl Urol. 2017 Oct;6(5):943-950. doi: 10.21037/tau.2017.09.01. Review.
Bladder pain in an LL-37 interstitial cystitis and painful bladder syndrome model.
Jia W, Schults AJ, Jensen MM, Ye X, Alt JA, Prestwich GD, Oottamasathien S.
Am J Clin Exp Urol. 2017 Sep 1;5(2):10-17. eCollection 2017.
Combination of Extracorporeal Shockwave Lithotripsy and Ureteroscopy for Large Staghorn Calculi in a Pediatric Patient: Case Report.
Schults AJ, Jia W, Ost MC, Oottamasathien S.
J Endourol Case Rep. 2017 May 1;3(1):64-66. doi: 10.1089/cren.2017.0029. eCollection 2017.
Silk-elastinlike protein polymers enhance the efficacy of a therapeutic glycosaminoglycan for prophylactic treatment of radiation-induced proctitis.
Jensen MM, Jia W, Isaacson KJ, Schults A, Cappello J, Prestwich GD, Oottamasathien S, Ghandehari H.
J Control Release. 2017 Oct 10;263:46-56. doi: 10.1016/j.jconrel.2017.02.025. Epub 2017 Feb 21.
Childhood Cancer Risk in the Siblings and Cousins of Men with Poor Semen Quality.
Anderson RE, Hanson HA, Lowrance WT, Redshaw J, Oottamasathien S, Schaeffer A, Johnstone E, Aston KI, Carrell DT, Cartwright P, Smith KR, Hotaling JM.
J Urol. 2017 Mar;197(3 Pt 2):898-905. doi: 10.1016/j.juro.2016.09.110. Epub 2017 Jan 26.
Prevention of sinonasal inflammation by a synthetic glycosaminoglycan.
Pulsipher A, Qin X, Thomas AJ, Prestwich GD, Oottamasathien S, Alt JA.
Int Forum Allergy Rhinol. 2017 Feb;7(2):177-184. doi: 10.1002/alr.21865. Epub 2016 Nov 11.
Topical cathelicidin (LL-37) an innate immune peptide induces acute olfactory epithelium inflammation in a mouse model.
Alt JA, Qin X, Pulsipher A, Orb Q, Orlandi RR, Zhang J, Schults A, Jia W, Presson AP, Prestwich GD, Oottamasathien S.
Int Forum Allergy Rhinol. 2015 Dec;5(12):1141-50. doi: 10.1002/alr.21634. Epub 2015 Sep 8.
PubMed PMID: 26346056
LL-37 induced cystitis and the receptor for advanced glycation end-products (RAGE) pathway.
Roundy LM, Jia W, Zhang J, Ye X, Prestwich GD, Oottamasathien S.
Adv Biosci Biotechnol. 2013 Aug 1;4(8B):1-8.
PubMed PMID: 24883227
Physiological relevance of LL-37 induced bladder inflammation and mast cells.
Oottamasathien S, Jia W, Roundy LM, Zhang J, Wang L, Ye X, Hill AC, Savage J, Lee WY, Hannon AM, Milner S, Prestwich GD.
J Urol. 2013 Oct;190(4 Suppl):1596-1602. doi: 10.1016/j.juro.2013.01.002. Epub 2013 Jan 9.
PubMed PMID: 23313203
Prevention of Anti-microbial Peptide LL-37-Induced Apoptosis and ATP Release in the Urinary Bladder by a Modified Glycosaminoglycan.
Lee WY, Savage JR, Zhang J, Jia W, Oottamasathien S, Prestwich GD, Thumbikat P, ed.
PLoS ONE. 2013;8(10):e77854. doi:10.1371/journal.pone.0077854.
A murine model of inflammatory bladder disease: cathelicidin peptide induced bladder inflammation and treatment with sulfated polysaccharides.
Oottamasathien S, Jia W, McCoard L, Slack S, Zhang J, Skardal A, Job K, Kennedy TP, Dull RO, Prestwich GD.
J Urol. 2011 Oct;186(4 Suppl):1684-92. doi: 10.1016/j.juro.2011.03.099. Epub 2011 Aug 19.
PubMed PMID: 21855919
Padded self-adhesive strap immobilization following newborn bladder exstrophy closure: the Utah straps.
Wallis MC, Oottamasathien S, Wicher C, Hadley D, Snow BW, Cartwright PC
J Urol. 2013 Dec;190(6):2216-20. doi: 10.1016/j.juro.2013.06.041. Epub 2013 Jun 26.
PubMed PMID: 23810641
Pediatric urinary stone composition in the United States.
Gabrielsen JS, Laciak RJ, Frank EL, McFadden M, Bates CS, Oottamasathien S, Hamilton BD, Wallis MC.
J Urol. 2012 Jun;187(6):2182-7. doi: 10.1016/j.juro.2012.01.124. Epub 2012 Apr 12.
PubMed PMID: 22503021
Parameatal urethral cysts in prepubertal males.
Willis HL, Snow BW, Cartwright PC, Wallis MC, Oottamasathien S, deVries C.
J Urol. 2011 Mar;185(3):1042-5. doi: 10.1016/j.juro.2010.10.038. Epub 2011 Jan 19. Review.
PubMed PMID: 21247599
Metastatic Crohn's disease of the penis in a pediatric patient.
Pohl JF, Comstock JM, Oottamasathien S.
Inflamm Bowel Dis. 2011 Apr;17(4):1056. doi: 10.1002/ibd.21408.
PubMed PMID: 20645314
250 consecutive unilateral extravesical ureteral reimplantations in an outpatient setting.
Wicher C, Hadley D, Ludlow D, Oottamasathien S, Wallis MC, Devries C, Snow BW, Cartwright PC.
J Urol. 2010 Jul;184(1):311-4. doi: 10.1016/j.juro.2010.01.056. Epub 2010 May 20.
PubMed PMID: 20488495
Temporal-spatial protein expression in bladder tissue derived from embryonic stem cells.
Thomas JC, Oottamasathien S, Makari JH, Honea L, Sharif-Afshar AR, Wang Y, Adams C, Wills ML, Bhowmick NA, Adams MC, Brock JW 3rd, Hayward SW, Matusik RJ, Pope JC 4th.
J Urol. 2008 Oct;180(4 Suppl):1784-9. doi: 10.1016/j.juro.2008.03.098. Epub 2008 Aug 21.
Prostate epithelial cell fate.
Matusik RJ, Jin RJ, Sun Q, Wang Y, Yu X, Gupta A, Nandana S, Case TC, Paul M, Mirosevich J, Oottamasathien S, Thomas J.
Differentiation. 2008 Jul;76(6):682-98. doi: 10.1111/j.1432-0436.2008.00276.x. Epub 2008 May 7. Review.
PubMed PMID: 18462434
Urothelial inhibition of transforming growth factor-beta in a bladder tissue recombination model.
Oottamasathien S, Williams K, Franco OE, Wills ML, Thomas JC, Sharif-Afshar AR, DeMarco RT, Brock JW 3rd, Bhowmick NA, Hayward SW, Pope JC 4th.
J Urol. 2007 Oct;178(4 Pt 2):1643-9. Epub 2007 Aug 16.
PubMed PMID: 17707033
Testicular tumours in children: a single-institutional experience.
Oottamasathien S, Thomas JC, Adams MC, DeMarco RT, Brock JW 3rd, Pope JC 4th.
BJU Int. 2007 May;99(5):1123-6.
PubMed PMID: 17437431
Directed differentiation of embryonic stem cells into bladder tissue.
Oottamasathien S, Wang Y, Williams K, Franco OE, Wills ML, Thomas JC, Saba K, Sharif-Afshar AR, Makari JH, Bhowmick NA, DeMarco RT, Hipkens S, Magnuson M, Brock JW 3rd, Hayward SW, Pope JC 4th, Matusik RJ.
Dev Biol. 2007 Apr 15;304(2):556-66. Epub 2007 Jan 12.
PubMed PMID: 17289017
Primary extrarenal nephroblastomatosis.
Oottamasathien S, Wills ML, Brock JW 3rd, Pope JC 4th.
Urology. 2007 Jan;69(1):184.e3-4.
PubMed PMID: 17270650
Bladder tissue formation from cultured bladder urothelium.
Oottamasathien S, Williams K, Franco OE, Thomas JC, Saba K, Bhowmick NA, Staack A, Demarco RT, Brock JW 3rd, Hayward SW, Pope JC 4th.
Dev Dyn. 2006 Oct;235(10):2795-801.
PubMed PMID: 16804891
Gonadoblastoma and Turner syndrome.
Brant WO, Rajimwale A, Lovell MA, Travers SH, Furness PD 3rd, Sorensen M, Oottamasathien S, Koyle MA.
J Urol. 2006 May;175(5):1858-60.
PubMed PMID: 16600779
Laparoscopic Palomo varicocele ligation in children and adolescents: results of 103 cases.
Koyle MA, Oottamasathien S, Barqawi A, Rajimwale A, Furness PD 3rd.
J Urol. 2004 Oct;172(4 Pt 2):1749-52; discussion 1752.
PubMed PMID: 15371805
Recent advances in hormonal therapy for advanced prostate cancer.
Oottamasathien S, Crawford ED.
Oncology (Williston Park). 2003 Aug;17(8):1047-52; discussion 1054-8. Review.
PubMed PMID: 12966672
The Oottamasathien Laboratory Massachusetts General Hospital/MassGeneral Hospital for Children Harvard Medical School
Pediatric Surgical Research Laboratories The Simches Research Center Charles River Plaza North 185 Cambridge Street, CPZN 6.200 Boston, MA 02114
Email the Oottamasathien Laboratory
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