Impact of N-Acetylgalactosamine-4-Sulfatase (Arylsulfatase B) on the Progression of Melanoma

N-乙酰半乳糖胺-4-硫酸酯酶(芳基硫酸酯酶 B)对黑色素瘤进展的影响

基本信息

  • 批准号:
    10258903
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-07-01 至 2025-06-30
  • 项目状态:
    未结题

项目摘要

The morbidity and mortality of malignant melanoma are significant problems for veterans, their families, and the general public. Progress has been made in early diagnosis and in treatment, in particular with advances in checkpoint inhibition therapy. However, not all patients respond to this approach and the treatment has major toxicity. There is a continuing unmet need for improvement in treatment of melanoma. This project presents a novel and potentially breakthrough treatment approach, based on the impact of the enzyme N- acetylgalactosamine-4-sulfatase, also known as arylsulfatase B (ARSB). This enzyme removes sulfate groups from chondroitin 4-sulfate (C4S) and dermatan sulfate and is required for the degradation of these sulfated glycosaminoglycans. Our previous work has shown that lower ARSB activity is associated with more aggressive melanomas. Also, decline in ARSB leads to increased expression of the melanoma proteoglycan chondroitin sulfate proteoglycan (CSPG)4 and of the matrix metalloproteinase pro-MMP2 which facilitates invasion. Other experiments have shown increase in PD-L1 expression in melanoma cells following ARSB silencing. In this project, we will determine the transcriptional mechanism by which decline in ARSB increases expression of PD-L1 in normal melanocytes and melanoma cells. Experiments will show how decline and increase in ARSB affect melanoma cell survival and intracellular signaling. The impact of anti-PD1 treatment on melanoma cell survival will be tested in live cell co-culture with immune cells following ARSB silencing. Other studies in the B16F10 and YUMM mouse models of melanoma and in a humanized mouse xenograft model will show the impact of modulation of ARSB in association with checkpoint inhibitor treatment on the progression of primary and metastatic melanomas. This project is based on over 30 publications in which Dr. Tobacman and collaborators have identified biological consequences of decline in ARSB. A previous report with project collaborator, Arkadiusz Dudek, M.D., Ph.D., a distinguished oncologist and investigator with strong interest, background, and clinical experience in immuno-oncology, identified decline in ARSB with increasing aggressiveness of melanoma cell lines, as well as significant increases in expression CSPG4 and pro-MMP2. Inborn deficiency of ARSB is present in the lysosomal storage disease Mucopolysaccharidosis (MPS) VI, in which mutations lead to marked reduction of ARSB activity. In malignant cells from prostate, breast, colon, and liver, as well as in melanoma cells and tissue, we have shown that expression and activity of ARSB are reduced, compared to normal melanocytes and tissue. Decline in ARSB leads to accumulation of the sulfated glycosaminoglycans chondroitin 4-sulfate and dermatan sulfate, from which ARSB normally removes the 4- sulfate group at the non-reducing end and is required to initiate their degradation. With decline in ARSB, C4S accumulates and its interactions with critical molecules are disrupted. We have shown that galectin-3, a co- transcriptional activator which binds to other important molecules, including the insulin receptor, binds less to more highly sulfated C4S and has increased nuclear translocation and interaction with transcription factors. Inversely, SHP2 (PTPN11), the ubiquitous non-membrane Src homology region 2 (SH2)-containing protein tyrosine phosphatase 2, binds more with more highly sulfated C4S and is less available for dephosphorylation of critical signaling molecules, including phospho-ERK1/2. Hence, the transcriptional events arising from altered sulfation of C4S have profound impact on vital cellular processes. This project will provide new insight into how changes in ARSB, and the resulting changes in chondroitin 4-sulfation and signaling and transcriptional events, impact on melanoma progression and on response to checkpoint inhibition. The findings may lead to new approaches to treatment of melanoma and to improvement in response to checkpoint inhibition, resulting in reduced suffering, morbidity, and mortality from melanoma.
恶性黑色素瘤的发病率和死亡率是退伍军人,他们的家庭, 和公众。在早期诊断和治疗方面已经取得了进展,特别是 检查点抑制疗法然而,并不是所有的患者都对这种方法有反应,治疗有很大的困难。 毒性对于改善黑素瘤的治疗存在持续未满足的需求。该项目提出了一个 新的和潜在的突破性的治疗方法,基于酶N- 乙酰半乳糖胺-4-硫酸酯酶,也称为芳基硫酸酯酶B(ARSB)。这种酶可以去除硫酸基 从软骨素4-硫酸盐(C4 S)和硫酸皮肤素,是降解这些硫酸化 糖胺聚糖我们以前的工作表明,较低的ARSB活性与更具侵略性有关。 黑素瘤。此外,ARSB下降导致黑色素瘤蛋白多糖软骨素表达增加 硫酸蛋白聚糖(CSPG)4和促进侵袭的基质金属蛋白酶pro-MMP 2。其他 实验显示ARSB沉默后黑素瘤细胞中PD-L1表达增加。 在这个项目中,我们将确定ARSB下降增加的转录机制 PD-L1在正常黑素细胞和黑素瘤细胞中的表达。实验将展示如何下降和 ARSB增加影响黑素瘤细胞存活和细胞内信号传导。抗PD 1治疗对 黑色素瘤细胞存活将在ARSB沉默后与免疫细胞共培养的活细胞中测试。其他 在黑色素瘤的B16 F10和YUMM小鼠模型和人源化小鼠异种移植模型中的研究将 显示与检查点抑制剂治疗相关的ARSB调节对 原发性和转移性黑素瘤。该项目是基于30多个出版物,其中博士Tobacman和 合作者已经确定了ARSB下降的生物学后果。以前的报告与项目 合作者,Arkadiusz Dudek,医学博士,哲学博士、一位杰出的肿瘤学家和研究者, 背景和免疫肿瘤学的临床经验,确定了ARSB的下降, 黑色素瘤细胞系的侵袭性,以及CSPG 4和pro-MMP 2表达的显著增加。 先天性ARSB缺陷存在于溶酶体贮积病粘多糖沉积症(MPS)VI中, 其中突变导致ARSB活性显著降低。在前列腺,乳腺,结肠, 和肝脏,以及黑色素瘤细胞和组织中,我们已经表明,ARSB的表达和活性, 与正常黑素细胞和组织相比,减少。ARSB下降导致硫酸盐积累 糖胺聚糖4-硫酸软骨素和硫酸皮肤素,ARSB通常从中除去4-硫酸软骨素和硫酸皮肤素。 在非还原端的硫酸基团,并需要启动其降解。随着ARSB、C4 S 积累并破坏其与关键分子的相互作用。我们已经证明,半乳糖凝集素-3,一种共- 与其他重要分子(包括胰岛素受体)结合的转录激活因子, 更高度硫酸化的C4 S,并且具有增加的核转位和与转录因子的相互作用。 Inflammatory,SHP 2(PTPN 11),普遍存在的非膜Src同源区2(SH 2)包含蛋白 酪氨酸磷酸酶2,更多地与更高度硫酸化的C4 S结合,并且不太可用于去磷酸化 包括磷酸化ERK 1/2。因此,由改变的基因引起的转录事件 C4 S硫酸化对重要的细胞过程具有深远的影响。 该项目将提供新的见解如何在ARSB的变化,以及由此产生的变化,软骨素 4-硫酸化和信号传导和转录事件,对黑色素瘤进展和对 检查点抑制这些发现可能会导致新的方法来治疗黑色素瘤和改善 对检查点抑制的反应,导致黑色素瘤的痛苦、发病率和死亡率降低。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Joanne Kramer Tobacman其他文献

Joanne Kramer Tobacman的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Joanne Kramer Tobacman', 18)}}的其他基金

Impact of N-Acetylgalactosamine-4-Sulfatase (Arylsulfatase B) on the Progression of Melanoma
N-乙酰半乳糖胺-4-硫酸酯酶(芳基硫酸酯酶 B)对黑色素瘤进展的影响
  • 批准号:
    10399551
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
Impact of N-Acetylgalactosamine-4-Sulfatase (Arylsulfatase B) on the Progression of Melanoma
N-乙酰半乳糖胺-4-硫酸酯酶(芳基硫酸酯酶 B)对黑色素瘤进展的影响
  • 批准号:
    10664841
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:

相似海外基金

How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
  • 批准号:
    BB/Z514391/1
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
  • 批准号:
    2312555
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
  • 批准号:
    2327346
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
  • 批准号:
    ES/Z502595/1
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
  • 批准号:
    ES/Z000149/1
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
  • 批准号:
    23K24936
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
  • 批准号:
    2901648
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
  • 批准号:
    488039
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
    Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
  • 批准号:
    23K00129
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
  • 批准号:
    2883985
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
    Studentship
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了