Research Projects

5-alpha reductase 2 (5-AR2) is a Key Enzyme Responsible for Proper Development of Prostate Tissue

Inhibition of 5-AR2 has proven to be efficacious for management of urinary symptoms associated with benign prostatic hyperplasia (BPH). However, some patients are resistant to the therapeutic effects of 5-AR2 inhibitor for management of lower urinary tract symptoms. The laboratory of Aria Olumi, MD, has shown that 30 percent of benign human prostate samples did not express the 5-AR 2 protein. They have demonstrated that the promoter region of 5AR2 contains a CpG island that is methylated in benign prostate epithelial cells and in 39 percent of benign human prostate samples. Methylation of the 5AR2 promoter may account for low or absent expression of 5AR2 in human adult prostate tissues.

Publications:

Wang Z, Hu L, Salari K, Bechis S, Ge R, Wu S, Rassoulian C, Pham J, Wu CL, Tabatabaei S, Douglas SW, Olumi AF. Androgenic to estrogenic switch in human adult prostate gland is regulated by epigenetic silencing of steroid 5α-reductase 2. J Pathol. 2017 Sep 20. PMID: 28940538

Ge R, Wang Z, Bechis S, Otsetov A, Hua S, We S, Wu C, Tabatabaei S, Olumi A. DNA Methyl Transferase 1 Reduces Expression of 5-alpha Reductase 2 in the Aging Adult Prostate. Am J Pathol, 2015 Mar;185(3):870-82. PMID: 25700986

Bechis SK, Otsetov AG, Ge R, Wang Z, Vangel MG, Wu CL, Tabatabaei S, Olumi AF. Age and Obesity Promote Methylation and Suppression of 5-Alpha Reductase 2- Implications for Personalized Therapy in Benign Prostatic Hyperplasia. Journal of Urology, 2015; 194:1031-7. PMID: 25916673

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Molecular Mechanisms of Bladder Dysfunction Associated with Type 2 Diabetes

Diabetes mellitus (DM) affects seven percent of the US population. DM patients often have urologic symptoms such as voiding, recurrent urinary tract infections and erectile dysfunction. Diabetic bladder dysfunction is a common complication and affects up to 80 percent of patients with diabetes. The laboratory of Aria Olumi, MD, is conducting research aimed at identifying molecular changes that are responsible for diabetic bladder cystopathy, which causes bladder dysfunction, to help identify diabetic patients at risk of developing bladder dysfunction prior to presentation of the late stages of the disease. The lab is also evaluating the molecular pathways that lead to diabetic cystopathy to improve our understanding of bladder dysfunction, and help devise preventive strategies for secondary complications associated with type 2 diabetes.

Publications:

Wang Z, Cheng Z, Cristofaro V, Li J, Xiao X, Gomez P, Ge R, Gong E, Strle K, Sullivan M, Adam R, White M, and Olumi AF. Inhibition of TNF-α improves the bladder dysfunction that is associated with type 2 diabetes in mice. Diabetes, 2012, 61(8):2134-45. PMID: 22688336 

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Genetic Expression Profiles Associated with Prostate Cancer

The laboratory of Chin-Lee Wu, MD, PhD, is using laser capture microdissection and DNA microarray techniques to identify a 32-gene signature whose expression can be used to predict prostate cancer outcomes. A continuous risk index was developed that assesses individualized recurrence risk. The 32-gene risk index was validated in an independent, blinded set of post-radical prostatectomy tissue samples. The lab is now developing a new gene-based diagnostic test to guide clinical management of prostate cancer. The genes identified in this study may also be used as new therapeutic targets.

Publications:

Development and validation of a 32-gene prognostic index for prostate cancer progression. Wu CL, Schroeder BE, Ma XJ, Cutie CJ, Wu S, Salunga R, Zhang Y, Kattan MW, Schnabel CA, Erlander MG, McDougal WS. Proc Natl Acad Sci U S A. 2013 Apr 9;110(15):6121-6. PMC3625257

News:

Gene-expression signature may signify risk for recurrence, metastasis in prostate cancer

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Metabolomic Signature of Prostate Cancer

There is a clinical need to improve the method for imaging prostate cancer in vivo. In collaboration with Dr. Leo Cheng, Mass General Pathology and Radiology, the laboratory of Chin-Lee Wu has identified a metabolomic signature of prostate cancer. The lab is applying this signature in the development of an in vivo imaging technique for prostate cancer to help detect, localize and quantify prostate cancer.

Publications:

DeFeo EM, Wu CL, McDougal WS, Cheng LL. A decade in prostate cancer: from NMR to metabolomics. Nat Rev Urol. 2011 May 17;8(6):301-11. PMID: 21587223

Wu CL, Jordan KW, Ratai EM, Sheng J, Adkins CB, Defeo EM, Jenkins BG, Ying L, McDougal WS, Cheng LL. Metabolomic imaging for human prostate cancer detection. Sci Transl Med. 2010 Jan 27;2(16):16ra8. PMC2857699

Kaul D, Wu CL, Adkins CB, Jordan KW, Defeo EM, Habbel P, Peterson RT, McDougal WS, Pohl U, Cheng LL. Assessing prostate cancer growth with mRNA of spermine metabolic enzymes. Cancer Biol Ther. 2010 May 1;9(9):736-42. PMID: 20215859

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Androgen Receptor Co-activators Involved in Prostate Cancer

Most prostate cancer death is due to the development of androgen independence. The androgen receptor is responsible for cell growth in both androgen dependent and independent prostate cancers. The laboratory of Chin-Lee Wu, PhD, MD, has identified two novel androgen receptor co-activators that may be involved in the development of androgen independence in prostate cancer. Characterizing these androgen receptor co-activators may lead to new drug targets for androgen independent prostate cancer.

Publications:

Development and validation of a 32-gene prognostic index for prostate cancer progression. Wu CL, Schroeder BE, Ma XJ, Cutie CJ, Wu S, Salunga R, Zhang Y, Kattan MW, Schnabel CA, Erlander MG, McDougal WS. Proc Natl Acad Sci U S A. 2013 Apr 9;110(15):6121-6. PMC3625257

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Inflamatory pathways of interstitial cystitis/painful bladder syndrome

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. 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).

Publications:

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. PMID: 29034266

Alt JA, Qin X, Pulsipher A, Orb Q, Orlandi RR, Zhang J, Schults A, Jia W, Presson AP, Prestwich GD, Oottamasathien S.  Topical cathelicidin (LL-37) an innate immune peptide induces acute olfactory epithelium inflammation in a mouse model.  Int Forum Allergy Rhinol.  2015 Dec;5(12):1141-50. doi: 10.1002/alr.21634. Epub 2015 Sep 8. PubMed PMID: 26346056