Prostate cancer (PCa) is associated with advanced age, but how age contributes to PCa is unknown. Aging is characterized by a chronic, low-grade inflammation, termed ?inflamm-aging?. Data supporting the role of inflammation in PCa comes from a variety of fields, though the causal relationship between inflammaging and PCa is unknown. Inflamm-aging is often attributed to the progressive activation of immune cells over time. Recent studies have shown that interleukin (IL)-17 producing T helper (Th) 17 cell responses are elevated in aging humans and mice and describe a reciprocal relationship between Th17 and T regulatory (Treg) cells. We have recently shown that IL-17 promotes PCa formation and growth in Pten-null mice. However, the role of Th17 cell responses is poorly understood in human aging and age-related PCa. Our long-term goal is to identify mechanisms responsible for inflamm-aging that predispose men to develop PCa, and to find new targeted therapeutic interventions against PCa in the elderly. Our overall objective is to determine whether and how Th17 cell responses and Th17/Treg imbalance contributes to prostate carcinogenesis during aging. Our central hypothesis is that age-related elevated Th17 cell responses and Th17/Treg imbalance promotes prostate carcinogenesis. This hypothesis has been formulated based on our preliminary data that Th17 cytokines from aged mice promote PCa cell lines proliferation, migration, and invasion, and activate NF-kB signaling in PCa cell lines. To test this hypothesis and attain our overall objective, we propose to complete three specific aims:
Aim 1, determine the role of Th17 cells in the aging process that drive the development of PCa by using aged and non-aged mouse models with Th17 transcription factor Batf and Pten conditional KO background;
Aim 2, assess the efficacy of therapeutic targeting of Th17 cell responses (by using anti-IL-23p19 Abs) and Th17/Treg imbalance (by using small molecule inhibitor SR1555 that can suppress Th17 and stimulate Treg) in preventing PCa development in aged vs. non-aged Pten KO mice;
Aim 3, determine the association between Th17/Treg ratio and activation of NF-kB/ERK1/2 and human PCa progression. The approach is innovative in that the tumor growth can be compared in the same time interval post-Pten excision between aged and non-aged mice, and between mice with and without Th17 and their products. The concept has clinical significance as blocking Th17 responses has the potential to be developed into therapeutics in the prevention and/or treatment of PCa, and Th17/Treg markers can be utilized as prognostics of human PCa progression.
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