Project 1

Afferent and urothelial plasticity underlying bladder sensitization in prostatic inflammation

Project Leader: Naoki Yoshimura, M.D., Ph.D.

Summary

Project 1 of the program is entitled "Afferent and urothelial plasticity underlying bladder sensitization in prostatic inflammation" (Project Leader: Naoki Yoshimura, Department of Urology). Prostatic inflammation is considered to be an important component of benign prostate hyperplasia (BPH) in addition to androgen-mediated ‘‘static’’ prostate enlargement and ‘‘dynamic’’ α-adrenoceptor–mediated muscle tension. Previous studies also suggest that asymptomatic prostatic inflammation associated with the development of histological BPH in involved in the emergence of lower urinary tract symptoms (LUTS). Thus, the following three key aims utilize unique and innovative expertise available in Pittsburgh to identify the detailed mechanisms of bladder overactivity, urothelial dysfunction and afferent hyperexcitability after prostatic inflammation, which reportedly contribute to lower urinary tract symptoms (LUTS) in patients with benign prostatic hyperplasia (BPH). We will also aim to determine whether treatments of local NGF antisense application, COX-2 inhibition or 5α-reductase inhibition can reverse the pathological processes initiated by prostatic inflammation.

In this application, we propose to extend our previously NIDDK P20 research project (DK090919, PI: Wang) entitled “University of Pittsburgh Planning Center for Benign Prostate Hyperplasia Research”, by critical evaluation of new mechanisms and development of innovative treatment options for male LUTS induced by prostatic inflammation. For this purpose, we will utilize an animal model of prostatic inflammation induced by local injection of formalin, , which was developed in our previously funded P20 project. First, we will study the changes in bladder function and functional/molecular properties of afferent neurons innervating the prostate and/or bladder to identify the role of prostate-to-bladder afferent cross sensitization in the development of LUTS due to prostatic inflammation. Secondly, we will examine whether prostatic inflammation induces bladder urothelial dysfunction, which also contributes to LUTS development. Lastly, we will seek to elucidate whether intravesical application of NGF antisense conjugated with liposomes targeting urothelial NGF production, COX-2 inhibitors (celecoxib) or 5α-reductase inhibitors (finasteride) can reverse functional and molecular changes in the bladder, urothelium and prostate/bladder afferent pathways initiated by prostatic inflammation in the rat model.

The long-term objectives of the research program are to identify new and effective targets and methods for the treatment of LUTS associated with BPH. Project 1 will maximize the uses of the resources of Administrative and Tissue Cores, and has strong synergy with other projects.