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Promotion of photocarcinogenesis by the senescent field and mechanisms for field persistence

Promotion of photocarcinogenesis by the senescent field and mechanisms for field persistence
衰老场促进光致癌作用和场持久性机制
批准号:
10487791
负责人:
RAYMOND L KONGER
金额:
$0.0万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-07-01 至 2026-06-30

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中文摘要
翻译
暴露于阳光中的紫外线(UV)是皮肤癌的主要原因,它造成的死亡人数超过50万人
英文摘要
Exposure to the ultraviolet (UV) rays of sunlight is the primary cause of skin cancer, which kills greater than 20,000 U.S. individuals each year. Veterans are at increased risk for skin cancer development due to increased sun exposure during training and deployment. UV exposure also causes photoaging that results in cells acquiring a post-mitotic phenotype called senescence. In addition to sun exposure, age and treatment with immunosuppressants are the most significant risk factors for skin cancer development. In this proposal, we will examine our novel 2 component cancer field model of cutaneous carcinogenesis that links photoaging and immunosuppression to skin cancer development. Historically, the cancer field refers to multifocal areas of otherwise normal epithelium that are at increased risk for cancer development. This epithelial cancer field is characterized by the stepwise accumulation of mutations that eventually lead to malignant conversion. We have shown that UV induces a multifocal dermal senescent field that is characterized by inflammatory angiogenesis that can be visualized and measured by imaging the dermal hemoglobin (Hb) content. This dermal field persists & expands following cessation of UV treatments and predicts sites of overlying epidermal clonal expansion & tumor formation. In this proposal, we propose that a dermal field also exists and that the key characteristic of this dermal field is the presence of senescent cells. These senescent cells produce and secrete specific pro-inflammatory, mitogenic and immunomodulatory mediators that we propose drive the continued development of the overlying epithelial mutant field. However, the immune system can recognize and clear senescent cells (senescence surveillance). We predict that this immune-mediated clearance acts to suppress the effects of the senescent dermal field on tumor formation. We expect that treatment with immunosuppressive drugs would promote tumorigenesis by blocking immune-mediated clearance of dermal senescent cells. Transforming growth factor beta (TGF-β) is a cytokine that is necessary for UV-induced senescence and is produced by senescent cells. This TGF-β production can in turn result in the induction of senescence in nearby cells (bystander senescence). We propose that bystander senescence, in an immunosuppressed setting, provides a self-perpetuating mechanism that drives senescent field persistence AND expansion. Finally, not all immunosuppressive agents have the same capacity to promote skin cancer development. Cyclosporine A promotes skin cancer development, TGF-β production, and induces senescence. In contrast, sirolimus has a limited effect on skin cancer risk, is known to suppresses TGF-β production, and suppresses senescent cell formation and secretory activity. In this proposal, we will determine whether the UV- induced senescent field is necessary for skin cancer development, determine whether immunosuppressive therapy promotes senescent field development and persistence, and determine whether TGF-β signaling & bystander senescence play central roles in this process. This will be done in three aims: Aim 1: Determine whether senolytic therapy inhibits photocarcinogenesis and dermal field persistence. Examine whether senolytic therapy and loss of TGF-β signaling block the ability of cyclosporine A to enhance, and sirolimus to suppress, UV-induced tumor formation. Aim 2. Use single cell RNA sequencing (scRNAseq) and dermal whole transcriptome sequencing and differential expression analysis to characterize the differences between hyperemic and non-hyperemic foci. Aim 3. Determine whether cyclosporine A suppresses senescence surveillance and promotes bystander senescence in wildtype while sirolimus acts to suppress bystander senescence. The role of TGF-β on bystander senescence will also be assessed.
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会议论文
Regulation of cutaneous immune function and anti-tumor immune responses by PPARgamma-mediated transrepressive signaling
  • 批准号:
    9898276
  • 项目类别:
  • 资助金额:
    $0.0万
  • 财政年份:
    2017
  • 负责人:
    RAYMOND L KONGER
  • 依托单位:
Regulation of cutaneous immune function and anti-tumor immune responses by PPARgamma-mediated transrepressive signaling
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    10450626
  • 项目类别:
  • 资助金额:
    $0.0万
  • 财政年份:
    2017
  • 负责人:
    RAYMOND L KONGER
  • 依托单位:
Characterization of persistent hyperemic foci and their role in photocarcinogenes
Characterization of persistent hyperemic foci and their role in photocarcinogenes
国内基金
海外基金
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    2021
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  • 项目类别:
    青年科学基金项目
  • 资助金额:
    24.0万元
  • 批准年份:
    2020
  • 负责人:
    段真珍
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    18870435
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    2.0万元
  • 批准年份:
    1988
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    史树中
  • 依托单位: