The proposed planning Center brings together a multidisciplinary team to explore a new paradigm that incorporates fibrosis as a contributing factor to urinary dysfunction and lower urinary tract symptoms (LUTS) development and progression. This team comprises faculty from two schools within the University of Michigan - Medicine and Engineering - that provides broad expertise in laboratory-based studies of urologic disease (Macoska), clinical expertise in treating prostate disease (Hollingsworth) and genitourinary pathology (Kunju), and in soft tissue mechanics (Arruda). The Center team has designed feasibility studies that employ quantitative approaches designed to measure fibrotic changes in human and mouse tissues and cells and to assess whether these fibrotic changes alter tissue rigidity/stiffness and thereby contribute to urinary dysfunction. These studies will test the specific hypothesis that extracellular matrix (ECM) remodeling by accumulating myofibroblasts in the aging prostate effectively generates a fibrotic prostate tissue architecture that increases tissue rigidity and reduces urethral flexibility, resulting in urinary flow obstruction and LUTS. These studies are organized into three Specific Aims:
Specific Aim 1 will determine whether tissues from the peri-urethral area of the human prostate in aging men and particularity those with LUTS demonstrate changes in the extracellular matrix (ECM) consistent with fibrosis, and whether these changes are associated with increased tissue 'mechanical rigidity and stiffness.
Specific Aim 2 will elucidate which proteins secreted by aging prostate stroma contribute to myofibroblast differentiation and ECM dysfunction in vitro, and test therapeutic approaches to inhibit or reverse these changes.
Specific Aim 3 will determine whether Senescence-Accelerated Mouse Prone 6 (SAMP6) and/or KC Transgenic mice exhibit changes in the ECM consistent with fibrosis, whether these changes are associated with increased tissue mechanical rigidity and stiffness, whether these changes affect urinary flow, and whether this pathology is exacerbated by obesity in vivo. If successful, the results of these studies will open the door to a new approach to effectively treat LUTS especially among men who cannot tolerate or fail to respond to current medical therapeutic approaches.
Lower urinary tract symptoms (LUTS) are a costly and critically progressive medical problem for millions of aging American men. Current therapeutic approaches for LUTS are focused on the ablation of androgen or smooth muscle activity, but these are not effective for all patients. This application seeks to determine whether a new class of therapeutics targeting tissue fibrosis may be developed to treat LUTS.
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| Gharaee-Kermani, Mehrnaz; Kasina, Sathish; Moore, Bethany B et al. (2012) CXC-type chemokines promote myofibroblast phenoconversion and prostatic fibrosis. PLoS One 7:e49278 |
| Ma, Jinjin; Gharaee-Kermani, Mehrnaz; Kunju, Lakshmi et al. (2012) Prostatic fibrosis is associated with lower urinary tract symptoms. J Urol 188:1375-81 |
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| Macoska, Jill A (2011) Chemokines and BPH/LUTS. Differentiation 82:253-60 |
