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

• 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
• 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

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 炎性免疫应答决定心肌梗死（MI）后的心脏愈合，并且在时间上是 调节以启动伤口愈合和疤痕形成。最近的研究表明，除了 在心肌梗塞（MI）后，循环、脾和心脏炎性细胞（单核细胞， 巨噬细胞和T淋巴细胞）甚至在MI（慢性HF）后8周增加，并促进 病理性左心室（LV）重构。此外，我们和其他人已经表明，特定的 细胞类型，包括慢性HF期间的单核细胞/巨噬细胞或T细胞，可钝化LV重塑并防止 心脏功能进行性下降，表明免疫细胞在这种疾病中起着关键作用。这些 研究结果强调了确定特定分子机制的必要性，这些机制可以有针对性地抑制 用于治疗性免疫调节的病理性免疫激活。 最近的研究表明，CD 4 + T细胞对于有效愈合、新血管形成和 检查心肌梗死期间的过度纤维化。然而，全基因敲除小鼠模型（如CD 4-/-）未能考虑 从急性心肌梗死到慢性心力衰竭过程中的时空变化。的确，我们的前 研究表明，CD 4 + T细胞在慢性HF期间发生表型转变，促进LV 心肌梗死后4 - 8周，它们的消耗使进行性心肌梗死变钝， 心功能不全尽管如此，介导这种转变的分子特征， 从心肌梗死到慢性心力衰竭的病理变化尚不清楚。对心脏CD 4 + T细胞进行RNA测序 从雄性小鼠衰竭的心脏中进行流式分选，我们发现，与MI相反，HF期间T细胞活化， 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 鉴定了一种新型ERβ激动剂药物（OSU-ERb-012）。我们的初步数据显示，OSU-ERb-012是高度 有效抑制抗CD 3/CD 28（T细胞受体）介导的T细胞增殖和pro-CD 28的表达， 炎性细胞因子，离体和体内。此外，在10 mg/kg剂量下，OSU-ERb-012显著钝化了 MI后4 - 8周给药时，LV重塑和HF进展表明其治疗作用 功效因此，我们假设OSU-ERb-012选择性地抑制抗原活化的病理性CD 4+细胞， 临床可转化剂量的T细胞可改善LV重塑和进行性心功能不全， 提示ERβ激动剂可作为选择性免疫调节药物。我们将测试这个 假设：i）描述OSU-ERb-012在改善LV重塑中的剂量依赖性作用，ii）检验 OSU-ERb-012的保护作用是否通过T细胞特异性ERβ激动作用介导，以及iii） 鉴定OSU-ERb-012对心肌细胞功能和心脏生理学作用。