Novel Inhibitors for Temporal Modulation of T-Lymphocytes during Chronic Heart Failure

慢性心力衰竭期间 T 淋巴细胞时间调节的新型抑制剂

基本信息

批准号：
10638340
负责人：
Shyam Sunder Bansal
金额：
$ 8.97万
依托单位：
OHIO STATE UNIVERSITY
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：
2023-07-01 至 2023-09-10
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10638340
关键词：
Acute myocardial infarction Affect Agonist Animal Model Antigens Apoptosis Autoimmune Biological Products Blood Chemical Analysis Blood capillaries Breeding CD28 gene CD3 Antigens CD4 Positive T Lymphocytes Cardiac Cardiac Myocytes Cardiovascular system Cell Separation Cells Cellular biology Cicatrix Clinic Clinical Collaborations Congestive Heart Failure Data Disease Disease Progression Dose Drug Design Echocardiography Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptors Exhibits Female Fibrosis Flow Cytometry Genes Heart Heart Injuries Heart failure Human Hypertrophy Immune Immune response Immunohistochemistry Immunology Inflammation Inflammatory Knockout Mice Knowledge Left Ventricular Remodeling Macrophage Measures Mediating Molecular Molecular Profiling Mus Myocardial Infarction Myocardial Ischemia Myocardial dysfunction Pathologic Patients Pharmaceutical Preparations Phenotype Physiology Process Proliferating Property Publishing Receptor Signaling Role Scientist Signal Transduction Sorting Specificity T-Cell Activation T-Cell Proliferation T-Cell Receptor T-Lymphocyte Testing Therapeutic Toxic effect Training Translating Treatment Efficacy cell type clinical translation cytokine density healing heart function immune activation immune modulating agents immunoregulation improved in vivo induced pluripotent stem cell derived cardiomyocytes inhibitor male monocyte mouse model neovascularization novel novel therapeutics prevent programs protective effect restraint spatiotemporal transcriptome sequencing wound healing

项目摘要

Project Summary Inflammatory immune responses dictate cardiac healing post-myocardial infarction (MI) and are temporally regulated to initiate wound-healing and scar formation. Recent studies have shown that, in addition to immediately after myocardial infarction (MI), circulating, splenic and cardiac inflammatory cells (monocytes, macrophages, and T-lymphocytes) are augmented even at 8-weeks post-MI (chronic HF), and promote pathological left ventricular (LV) remodeling. Moreover, we and others have shown that depletion of specific cell types, including monocytes/macrophages or T-cells during chronic HF blunts LV remodeling and prevents progressive decline in cardiac function, suggesting a critical role of immune cells in this disease. These findings underscore the necessity for identifying specific molecular mechanisms that can be targeted to restrain pathological immune activation for therapeutic immune-modulation. Recent studies have shown that CD4+ T-cells are obligatory for efficient healing, neovascularization, and to check excessive fibrosis during MI. However, global knockout mouse models (such as CD4-/-) fail to consider spatio-temporal alterations that we see during progression from acute-MI to chronic HF. Indeed, our previous studies showed that CD4+ T-cells undergo a phenotypic shift specifically during chronic HF, promote LV remodeling in an antigen-dependent manner, and their depletion from 4 to 8 weeks post-MI blunts progressive cardiac dysfunction. Nonetheless, the molecular signatures that mediate this transition from being protective during MI to pathological during chronic HF are not known. Using RNA sequencing on cardiac CD4+ T-cells flow-sorted from the failing hearts of male mice, we showed that, as opposed to MI, T-cells activated during HF possess upregulated estrogen receptor (ER) α signaling. Since ERα effects are opposed by ERβ activation, we identified a novel ERβ agonistic drug (OSU-ERb-012). Our preliminary data show that OSU-ERb-012 is highly efficacious at inhibiting anti-CD3/CD28 (T-cell receptor) mediated T-cell proliferation and expression of pro- inflammatory cytokines, ex-vivo and in-vivo. Moreover, at 10 mg/kg dose OSU-ERb-012 significantly blunted LV remodeling and HF progression when administered from 4 to 8 weeks post-MI suggesting its therapeutic efficacy. Thus, we hypothesize that OSU-ERb-012 selectively inhibits antigenically activated pathological CD4+ T-cells at clinically translatable doses, ameliorate LV remodeling and progressive cardiac dysfunction during chronic HF, and that ERβ agonists could be used as selective immuno-modulatory drugs. We will test this hypothesis by i) delineating dose-dependent effects of OSU-ERb-012 in ameliorating LV remodeling, ii) testing whether the protective effects of OSU-ERb-012 are mediated through T-cell specific ERβ agonism, and iii) identify effects of OSU-ERb-012 on cardiomyocyte function and cardiac physiology.

项目摘要炎症性免疫复发决定心脏梗死后心脏愈合（MI），并暂时调节以启动伤口愈合和疤痕形成。最近的研究表明，除了心肌梗死（MI）后立即循环，脾和心脏炎症细胞（单核细胞，即使在MI后8周（慢性HF），巨噬细胞和T淋巴细胞也会增加，并促进病理左心室（LV）重塑。此外，我们和其他人表明了特定的深度细胞类型，包括慢性HF钝化LV重塑时的单核细胞/巨噬细胞或T细胞心脏功能的进行性下降，表明免疫细胞在该疾病中的关键作用。这些发现强调了可以识别可以针对的特定分子机制的必要条件病理免疫激活用于治疗性免疫调节。最近的研究表明，CD4+ T细胞对有效的愈合，新血管形成和对在MI期间检查过多的纤维化。但是，全局敲除鼠标模型（例如CD4 - / - ）无法考虑我们在从急性-MI到慢性HF的过程中看到的时空变化。的确，我们以前的研究表明，CD4+ T细胞在慢性HF期间专门进行表型转移，促进LV 以抗原依赖性方式进行重塑，并在MI钝后4周到8周的部署心脏功能障碍。但是，介导这种转变的分子特征是受到保护的在慢性HF期间MI到病理期间，尚不清楚。在心脏CD4+ T细胞上使用RNA测序从雄性小鼠的失败心脏流动的流动，我们表明，与MI相反，在HF期间激活了T细胞具有上调的雌激素受体（ER）α信号传导。由于ERα效应与ERβ激活相反，我们鉴定出一种新型的ERβ激动药（OSU-ERB-012）。我们的初步数据表明OSU-ERB-012高度有效抑制抗CD3/CD28（T细胞受体）介导的T细胞增殖和前表达炎症细胞因子，前体内和体内。此外，以10 mg/kg剂量OSU-ERB-012显着钝化在MI后4到8周施用LV重塑和HF进展，提示其治疗效率。这是我们假设OSU-ERB-012选择性抑制抗原活化的病理CD4+ 在临床上可翻译剂量的T细胞，改善LV重塑和进行性心脏功能障碍慢性HF，ERβ激动剂可以用作选择性免疫调节药物。我们将测试这个 i）描述OSU-ERB-012在改善LV重塑的剂量依赖性效应，ii）测试 OSU-ERB-012的受保护作用是否是通过T细胞特异性ERβ激动剂介导的，III）确定OSU-ERB-012对心肌细胞功能和心脏生理学的影响。