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

基本信息

批准号：
10658079
负责人：
Elizabeth P Henske
金额：
$ 53.9万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-05 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10658079
关键词：
Adult Angiomyolipoma Antibodies Area Autosomal Dominant Polycystic Kidney Benign Bilateral Body mass index CD276 gene CD8-Positive T-Lymphocytes Carcinoma Cause of Death Cell Proliferation Cell Surface Proteins Cell Survival Cell physiology Cells Cellular Indexing of Transcriptomes and Epitopes by Sequencing Cessation of life Child Childhood Chronic Clinical Clinical Trials Complex Couples Cyst Cystic kidney Data Development Disease Epithelium FRAP1 gene Fatty acid glycerol esters Genetic Growth Hemorrhage Homologous Gene Human Immune Immunological Models Immunosuppression In Vitro Individual Infection Kidney Kidney Diseases Knockout Mice Lead Lesion Life Lipids Macrophage Membrane Glycoproteins Morbidity - disease rate Morphology Mus Myeloid-derived suppressor cells Null Lymphocytes PKD1 gene Pathway interactions Patients Peptides Phenotype Play Polycystic Kidney Diseases Pre-Clinical Model Proteins Proteomics Renal Angiomyolipoma Renal Cell Carcinoma Seizures Smooth Muscle Specimen TSC1 gene TSC1/2 gene TSC2 gene Testing Therapeutic Tuberous Sclerosis Work antibody detection autosome cell growth clinical development early childhood human data immune checkpoint immunoregulation immunosuppressive macrophages improved in vivo infancy inhibitor innovation loss of function mutation mTOR inhibition mortality mouse model nano-string novel novel therapeutic intervention preclinical efficacy programmed cell death ligand 1 protein complex response single-cell RNA sequencing therapeutic target transcriptomic profiling tumor-immune system interactions

项目摘要

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 In unpublished data, we found increased immunosuppressive CD206-positive macrophages and high expression of the immune checkpoint molecule B7-H3 (a homolog of PD-L1) in human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).

抽象的结节性硬化症（TSC）是一种由种系功能丧失引起的常染色体显性遗传疾病 TSC1 或 TSC2 基因突变。肾脏疾病，包括血管平滑肌脂肪瘤、囊肿和癌，是 TSC 发病和死亡的第二大原因。在未发表的数据中，我们发现免疫抑制性 CD206 阳性巨噬细胞增多且高表达人 TSC 肾囊肿中免疫检查点分子 B7-H3（PD-L1 同源物）的变化血管平滑肌脂肪瘤。我们还证明 B7-H3 通过一种机制促进体内 TSC2 缺失细胞的生长这需要 CD8+ T 细胞。这些和其他数据引出了我们的中心假设：免疫抑制巨噬细胞与 B7-H3 一起 TSC2 缺陷细胞上的表达会促进 TSC 中的肾脏疾病。这个的一个关键的翻译推论假设免疫抑制巨噬细胞和 B7-H3 是 TSC 的潜在治疗靶点。目标 1：确定巨噬细胞导致肾脏表现的机制 TSC 的。我们将检验免疫抑制巨噬细胞促进 TSC1 和 TSC2 缺陷的假设直接和/或通过抑制 CD8+ T 细胞功能间接细胞生长。目标 2：确定 B7-H3 如何重塑 TSC 相关肾的免疫微环境疾病。我们将检验 B7-H3 通过抑制 CD8+ T 细胞功能促进 TSC2-null 细胞生长的假设。目标 3：研究联合靶向巨噬细胞和 B7-H3 在 TSC 中的临床前疗效。我们将测试假设同时针对免疫抑制性巨噬细胞和 B7-H3 将导致持久、持久的由 Tsc1 或 Tsc2 缺失驱动的肾脏疾病临床前模型中的反应。我们希望这个项目能够通过确定负责的免疫机制来产生科学影响。 TSC2 缺失细胞在肾脏中的生长。这些机制可能具有广泛的影响，因为巨噬细胞据信在其他肾脏疾病中发挥着关键作用，包括常染色体显性多囊肾病（ADPKD）。我们的创新领域包括新颖的、与转化相关的假设以及技术创新，包括 CITE-seq、空间 CODEX 和 nanoString 转录组分析，以及一种新颖的、未发表的 TSC 肾病小鼠模型 (Rosa26-CreERT2 Tsc2f/f)。