The Impact of Aging on Prostate Cancer with Age-Related Disruption of Th17/Treg Axis

衰老对前列腺癌的影响与年龄相关的 Th17/Treg 轴破坏

• 批准号: 10322027
• 负责人: Qiuyang Zhang
• 金额: $ 34.07万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10322027
• 关键词: Age; Age Factors; Aging; Antibodies; Blood; Blood Circulation; CD4 Positive T Lymphocytes; Case Fatality Rates; Cell Proliferation; Cell Survival; Cell physiology; Cells; Cessation of life; Chronic; Clinical; Clinical Trials; Data; Development; Disease; Elderly; Elderly man; Equilibrium; Etiology; Excision; Future; Goals; Human; Incidence; Inflammaging; Inflammation; Inflammatory; Knock-out; Knockout Mice; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mission; Molecular; Mus; Mutate; NF-kappa B; Outcome; Pathogenicity; Patients; Pharmacology; Play; Prevalence; Prevention; Process; Prognostic Marker; Prostate; Prostate Cancer therapy; Public Health; Regulatory T-Lymphocyte; Reporting; Research; Role; Specimen; Testing; Therapeutic; Therapeutic Intervention; Tissues; Translating; Treatment Efficacy; Tumor Suppressor Genes; United States National Institutes of Health; activating transcription factor; age related; aged; bZIP Domain; base; cancer initiation; clinically significant; comorbidity; evidence base; immune activation; innovation; migration; mortality; mouse model; new therapeutic target; novel; novel therapeutics; prevent; prognostic indicator; prostate cancer cell; prostate cancer prevention; prostate cancer progression; prostate carcinogenesis; response; small molecule; targeted agent; targeted treatment; therapeutic target; time interval; transcription factor; tumor; tumor growth; tumor progression

Project Summary/Abstract: Prostate cancer (PCa) is particularly important in elderly men because of the high incidence and prevalence of disease and mortality in this group of patients. Although the case-fatality rate of PCa is quite low, deaths occur disproportionately in the elderly. However, the reasons for the increased incidence and mortality due to PCa in elderly men are not entirely clear. Low-grade inflammation (i.e., inflammaging) plays an important role in the aging process, and chronic inflammation contributes to the onset and progression of PCa. Inflammaging is often attributed to the progressive activation of immune cells. In that regard, a disruption in the balance of pro-inflammatory Th17 cells and homeostatic regulatory T (Treg) cells in favor of Th17 cells was reported previously to occur in non-cancer-related aging in humans and mice. Preliminary data support that elderly human prostate tissue had increased Th17/Treg ratio and the similar phenomenon was found in aged mice circulation and prostate tissue, and CD4+ T cell secreted factors from aged mice compared to young mice promote PCa cell proliferation, migration, and invasion. The long-term goal is to contribute toward the development of novel clinically useful strategies to treat or prevent PCa associated with advanced aging. The overall objective in this proposal is to determine how age-related Th17/Treg imbalance contributes to prostate carcinogenesis. The central hypothesis is that age-related disruption of Th17/Treg axis promotes PCa initiation and progression. The rationale for the proposed research is that a determination of how Th17/Treg imbalance promotes prostate carcinogenesis is likely to provide new opportunities for the subsequent development of targeted therapeutics to the prevention/treatment of prostate cancers associated with advanced aging. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Identify associations between Th17/Treg ratio alteration and progression of human PCa associated with advanced aging. 2) Define how aging-associated imbalances in Th17/Treg axis drive PCa. 3) Determine the efficacy of therapeutic targeting of Th17/Treg axis in preventing aging-associated PCa. In aim 1, the expression of Th17/Treg and NF-kB will be examined in human normal and PCa specimens at different ages. In aim 2, the Batf and Pten (tumor suppressor gene) double knockout mouse model generated at different ages will be used to assess whether Batf status and age plays a critical role in PCa initiation and progression. In aim 3, the anti- IL-23p19 antibody and small molecule SR1555 (both suppress Th17/stimulate Treg function) will be tested. The approach is innovative, in the applicant’s opinion, because the tumor growth can be compared in the same time interval post-Pten excision between the aged and non-aged mice. The proposed research is significant, as the concept is novel and has clinical significance because rectifying Th17/Treg imbalance has the potential to be developed into prognostic indicator of PCa and therapeutics in the prevention and treatment of PCa in the elderly.

项目概要/摘要： 前列腺癌（PCa）在老年男性中特别重要，因为其发病率高， 这组患者的患病率和死亡率。虽然PCa的病死率很低， 老年人的死亡比例过高。然而，发病率和死亡率增加的原因 老年男性前列腺癌的病因尚不完全清楚。低度炎症（即，炎症）扮演一个 PCa在衰老过程中起重要作用，慢性炎症有助于PCa的发生和进展。 炎症通常归因于免疫细胞的进行性激活。在这方面， 促炎性Th 17细胞和稳态调节性T（Treg）细胞的平衡有利于Th 17细胞， 先前报道在人类和小鼠的非癌症相关衰老中发生。初步数据显示， 老年人前列腺组织中Th 17/Treg比值升高，老年人前列腺组织中Th 17/Treg比值升高。 小鼠循环和前列腺组织，以及老年小鼠与年轻小鼠相比的CD 4 + T细胞分泌因子 促进PCa细胞增殖、迁移和侵袭。长期目标是促进 开发新的临床有用的策略来治疗或预防与晚期衰老相关的PCa。的 本提案的总体目标是确定年龄相关的Th 17/Treg失衡如何有助于前列腺增生 致癌作用中心假设是年龄相关的Th 17/Treg轴破坏促进PCa启动 和进步。提出的研究的基本原理是，确定Th 17/Treg失衡是如何发生的， 促进前列腺癌的发生可能为以后的发展提供新的机会， 用于预防/治疗与晚期衰老相关的前列腺癌的靶向治疗剂。指导 通过强有力的初步数据，这一假设将通过追求三个具体目标来检验：1）确定 Th 17/Treg比值改变与晚期前列腺癌进展的关系 衰老2)定义Th 17/Treg轴中老化相关失衡如何驱动PCa。3)确定brigatinib的疗效 治疗靶向Th 17/Treg轴预防衰老相关PCa。在目标1中， 将在不同年龄的人正常和PCa标本中检测Th 17/Treg和NF-kB。在目标2中， 将使用在不同年龄产生的Batf和Pten（肿瘤抑制基因）双敲除小鼠模型 评估Batf状态和年龄是否在PCa发生和进展中起关键作用。在目标3中，反 将检测IL-23 p19抗体和小分子SR 1555（均抑制Th 17/刺激Treg功能）。 在申请人看来，该方法是创新的，因为肿瘤生长可以在相同条件下进行比较。 老年和非老年小鼠之间Pten切除后的时间间隔。拟议的研究意义重大， 因为该概念是新颖的并且具有临床意义，因为纠正Th 17/Treg失衡具有潜在的 有望发展成为前列腺癌的预后指标和前列腺癌的预防和治疗药物， 老人