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Mechanisms of immunosuppression in the development and progression of renal disease in Tuberous Sclerosis Complex

Mechanisms of immunosuppression in the development and progression of renal disease in Tuberous Sclerosis Complex
免疫抑制在结节性硬化症肾病发生和进展中的机制
批准号:
10658079
负责人:
Elizabeth P Henske
金额:
$53.9万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-04-05 至 2028-03-31

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中文摘要
翻译
摘要 多发性硬化症(TSC)是一种由生殖细胞功能丧失引起的常染色体显性遗传疾病 TSC 1或TSC 2基因突变。肾脏疾病,包括血管平滑肌脂肪瘤、囊肿和癌, 是TSC发病率和死亡率的第二大原因。 在未发表的数据中,我们发现免疫抑制性CD 206阳性巨噬细胞和高表达 免疫检查点分子B7-H3(PD-L1的同源物)在人TSC肾囊肿中的作用, 血管平滑肌脂肪瘤我们还证明,B7-H3通过一种机制在体内促进TSC 2缺失细胞的生长 需要CD 8 + T细胞 这些和其他数据导致我们的中心假设:免疫抑制性巨噬细胞与B7-H3 TSC 2缺陷细胞上的表达促进TSC中的肾病。一个关键的翻译推论是, 假设免疫抑制性巨噬细胞和B7-H3是TSC的潜在治疗靶点。 目的1:确定巨噬细胞参与肾脏表现的机制 关于TSC我们将检验免疫抑制巨噬细胞促进TSC 1和TSC 2缺陷的假设。 直接和/或通过抑制CD 8 + T细胞功能间接抑制细胞生长。 目的2:确定B7-H3如何重塑TSC相关肾肿瘤的免疫微环境。 疾病我们将检验B7-H3通过抑制CD 8 + T细胞功能促进TSC 2无效细胞生长的假设。 目的3:研究共同靶向巨噬细胞和B7-H3在TSC中的临床前疗效。我们将测试 假设靶向免疫抑制性巨噬细胞和B7-H3将导致持久的,持久的 Tsc 1或Tsc 2缺失导致的肾脏疾病临床前模型中的反应。 我们希望这个项目通过确定负责免疫机制的科学影响, 肾脏中缺乏TSC 2的细胞的生长。这些机制可能具有广泛的意义,因为巨噬细胞 被认为在其他肾脏疾病中起关键作用,包括常染色体显性多囊肾病 (ADPKD)。我们的创新领域包括我们新颖的、相关的假设以及技术创新。 创新,包括CITE-seq,空间CODEX和nanoString转录组学分析,以及一种新的,未发表的 TSC(Rosa 26-CreERT 2 Tsc 2f/f)中的肾病小鼠模型。
英文摘要
Abstract Tuberous sclerosis complex (TSC) is an autosomal dominant disease caused by germline loss-of-function mutations in the TSC1 or TSC2 gene. Renal disease, which includes angiomyolipomas, cysts, and carcinomas, is the second leading cause of morbidity and mortality in TSC. In unpublished data, we found increased immunosuppressive CD206-positive macrophages and high expression of the immune checkpoint molecule B7-H3 (a homolog of PD-L1) in human TSC renal cysts and angiomyolipomas. We also demonstrate that B7-H3 promotes TSC2-null cell growth in vivo via a mechanism that requires CD8+ T cells. These and other data lead to our central hypothesis: immunosuppressive macrophages together with B7-H3 expression on TSC2-deficient cells promote renal disease in TSC. A key translational corollary of this hypothesis is that immunosuppressive macrophages and B7-H3 are potential therapeutic targets for TSC. Aim 1: To identify the mechanisms through which macrophages contribute to the renal manifestations of TSC. We will test the hypothesis that immunosuppressive macrophages promote TSC1- and TSC2-deficient cell growth directly, and/or indirectly via inhibition of CD8+ T cell function. Aim 2: To determine how B7-H3 remodels the immune microenvironment of TSC-associated renal disease. We will test the hypothesis that B7-H3 promotes TSC2-null cell growth by inhibiting CD8+ T cell function. Aim 3: To investigate the preclinical efficacy of co-targeting macrophages and B7-H3 in TSC. We will test the hypothesis that targeting both immunosuppressive macrophages and B7-H3 will lead to long-lasting, durable responses in preclinical models of renal disease driven by loss of Tsc1 or Tsc2. We expect this project to have scientific impact by identifying the immune mechanisms responsible for the growth of TSC2-null cells in the kidney. These mechanisms may have broad implications, since macrophages are believed to play a key role in other renal diseases, including autosomal dominant polycystic kidney disease (ADPKD). Our areas of innovation include our novel, translationally relevant hypotheses as well as technical innovation, including CITE-seq, spatial CODEX and nanoString transcriptomic profiling, and a novel, unpublished mouse model of renal disease in TSC (Rosa26-CreERT2 Tsc2f/f).
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Role of the Lysosome in the Pathogenesis and Therapy of LAM
  • 批准号:
    10214679
  • 项目类别:
  • 资助金额:
    $43.95万
  • 财政年份:
    2020
  • 负责人:
    Elizabeth P Henske
  • 依托单位:
Role of the Lysosome in the Pathogenesis and Therapy of LAM
  • 批准号:
    10633178
  • 项目类别:
  • 资助金额:
    $43.95万
  • 财政年份:
    2020
  • 负责人:
    Elizabeth P Henske
  • 依托单位:
Role of the Lysosome in the Pathogenesis and Therapy of LAM
  • 批准号:
    10431886
  • 项目类别:
  • 资助金额:
    $43.95万
  • 财政年份:
    2020
  • 负责人:
    Elizabeth P Henske
  • 依托单位:
Pathogenic Mechanisms of Pulmonary Lymphangioleiomyomatosis
海外基金