Tackling the MARCKS-PIP3 Circuit to Attenuate Chronic Pulmonary Fibrosis

解决 MARCKS-PIP3 回路以减轻慢性肺纤维化

• 批准号: 10152291
• 负责人: Reen Wu
• 金额: $ 34.77万
• 依托单位: EFFECTORBIO, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10152291
• 关键词: AKT Signaling Pathway; Adoptive Transfer; Age; Animal Model; Animals; Attenuated; Bleomycin; Canis familiaris; Cells; Chronic; Clinic; Clinical; Clinical Drug Development; Collagen; Deposition; Diagnosis; Disease; Drug Kinetics; Epithelial; Event; Exhibits; Extracellular Matrix; FDA approved; Failure; Felis catus; Fibroblasts; Future; Growth; Human; In Vitro; Inflammatory; Injury; Legal patent; Lesion; Longevity; Lung; Lung diseases; MARCKS gene; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mesenchymal; Mus; Myofibroblast; Pathogenesis; Pathogenicity; Pathologic; Patients; Peptides; Personal Satisfaction; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Phase; Phosphorylation; Phosphorylation Site; Pirfenidone; Process; Protein Tyrosine Kinase; Proto-Oncogene Proteins c-akt; Publications; Pulmonary Fibrosis; RNA; Research; Signal Transduction; Small Business Innovation Research Grant; Structure of parenchyma of lung; System; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Time; Tissues; aged; base; clinical development; drug testing; fibrogenesis; humanized mouse; idiopathic pulmonary fibrosis; in vivo; indium-bleomycin; inhibitor/antagonist; injury and repair; innovation; lung injury; macrophage; monocyte; mouse model; novel; peptidomimetics; protein biomarkers; pulmonary function; receptor; stem; success; therapeutic evaluation; wortmannin

Project Summary Lung fibrosis is an important step of normal lung injury-repair process. However, uncontrolled injury and repair, and excessive deposition of collagen in the lung parenchyma is the pathological hallmark of chronic pulmonary fibrosis, such as idiopathic pulmonary fibrosis (IPF). The disease exhibits a median survival time of only 3 to 5 years from the time of diagnosis. Currently, there is no suitable drug for the treatment, except two drugs: Nintedanib and Pirfenidone, approved by FDA. However, adverse and off-target effects, and failure to demonstrate increased longevity in treated patients indicate the urgent need for new and better therapeutic agent(s) to treat this devastating disease. Epithelial-mesenchymal (EM) and fibroblast-myofibroblast (FM) transitions have been implicated in the initiation and the progression of fibrotic lung pathogenesis. The EM and FM transition phenomena, important pathogenic events associated with cancer malignancy, are primordially and mainly mediated by receptor-mediated tyrosine kinase (RTK) and PI3K-AKT signaling pathways. We have shown before the elevation of phospho-MARCKS in lung cancer tissues/cells associated with EM transition and the use of a peptide inhibitor, MPS (MARCKS PSD/ED Sequence), to suppress EM transition and lung cancer malignancy through tackling the aberrant MARCKS-PIP3 circuit associated with cancer pathogenesis. The elevated phospho-MARCKS phenomenon is also seen in tissue sections and isolated fibroblasts derived from IPF lungs, but not seen in any normal, non-fiberotic ones. Our recent publication had shown the therapeutic potential of MPS peptide in the suppression of the fibrotic lesions in bleomycin-induced fibrotic mouse lungs. In vitro, MPS tackles the aberrant MARCKS-PIP3 circuit to suppress MARCKS phosphorylation and also selectively inhibits the EM/FM transition and myofibroblast fibrogenesis, as well as the alteration of M1/M2 macrophage polarization. The selectivity occurs only on IPF-derived fibroblasts and activated macrophage, but not on the normal and inactivated monocytes. Through peptide optimization, we have developed further a stable, more biosafe, and high potency of a novel MPS-derived peptide, MPS-6413DTM. Initial studies have shown the efficacy of this peptide on the suppression of bleomycin-induced lung fibrotic lesions and deceased in mice, but not on the control ones. We hypothesize that MPS-6413D is a potent anti-fibrotic lung drug on the inhibition of fibrogenic progression of chronic lung fibrosis through tackling the MARCKS-PIP3 circuit. To test this hypothesis and the therapeutic potential of this peptide, two aims are proposed. Aim 1 is to determine further the therapeutic effects of MPS-6413D peptide on bleomycin induced lung fibrotic lesions in aged 32-week old (equivalent to 42 years old human) mice. The therapeutic potency will be determined on the inhibition of the expression of profibrogenic marker proteins and their RNA, and the inhibition of MARCKS and its phosphorylation in total lung homogenates, matrix deposition, pulmonary function, and also the overall survival and well-being in these age mice after bleomycin exposure. Aim 2 is to evaluate an inhibitory effect of MPS-6413D peptide on fibrogenic activity of IPF lung fibroblasts in humanized mouse model. To better reflect clinical scenarios, IPF human lung fibroblasts (HLFs) will be adoptively transferred to C.B-17 SCID/bg mice in order to test the therapeutic potential of MPS in lung fibrosis. Success of these studies will lead to the submission of the Phase II SBIR study on animals with spontaneous lung fibrosis, the pharmacodynamic/pharmacokinetic analysis, an IND-based study to FDA for future clinical drug development to attenuate chronic pulmonary fibrosis.

项目摘要 肺纤维化是正常肺损伤治疗过程的重要步骤。但是，不受控制的伤害和维修， 胶原蛋白在肺实质中的过度沉积是慢性肺的病理标志 纤维化，例如特发性肺纤维化（IPF）。该疾病的中位生存时间仅为3至5 从诊断开始的几年。目前，除两种药物外，没有合适的药物用于治疗： Nintedanib和Pirfenidone，由FDA批准。但是，不利目标效果以及未能 证明治疗患者的寿命增加表明迫切需要新的治疗方法 药物治疗这种毁灭性疾病。上皮 - 间质（EM）和成纤维细胞成纤维纤维细胞（FM） 过渡与纤维化肺发病机理的起始和进展有关。 Em和 FM过渡现象，与癌症恶性肿瘤相关的重要致病事件，是原始的， 主要由受体介导的酪氨酸激酶（RTK）和PI3K-AKT信号通路介导。我们已经显示了 在与EM转变相关的肺癌组织/细胞中磷酸 - 马克斯的升高之前 肽抑制剂MPS（MARCKS PSD/ED序列）的抑制和肺癌 通过解决与癌症发病机理相关的异常MARCKS-PIP3电路的恶性肿瘤。这 在组织切片和衍生自分离的成纤维细胞中也可以看到升高的磷酸化现象 IPF肺，但在任何普通的非纤维化肺部都没有看到。我们最近的出版物表明了治疗性 MPS肽在抑制博来霉素诱导的纤维化小鼠肺中的纤维化病变中的潜力。在 体外，MPS应对异常的MARCKS-PIP3电路以抑制Marcks磷酸化，并有选择地 抑制EM/FM过渡和肌纤维细胞纤维发生，以及M1/M2巨噬细胞的改变 极化。选择性仅发生在IPF衍生的成纤维细胞和激活的巨噬细胞上，但不在 正常和灭活的单核细胞。通过肽优化，我们开发了一个稳定的，更多的 新型MPS衍生的肽MPS-6413DTM的生物安全和高效力。最初的研究表明了功效 这种肽在抑制博来霉素诱导的肺纤维化病变并在小鼠中死亡，但不在 控制。我们假设MPS-6413D是一种抑制纤维化的有效抗纤维化肺部药物 通过应对MARCKS-PIP3电路的慢性肺纤维化进展。检验这一假设和 该肽的治疗潜力提出了两个目标。目标1是进一步确定治疗效果 在32周大的博来霉素上的MPS-6413D肽的诱导肺纤维化病变（相当于42岁） 老人）小鼠。治疗效力将确定抑制纤维化的表达 标记蛋白及其RNA，以及对MARCKS的抑制及其在总肺匀浆中的磷酸化， 基质沉积，肺功能以及这些年龄小鼠的总体生存和福祉 博来霉素暴露。 AIM 2是评估MPS-6413D肽对IPF纤维化活性的抑制作用 人性化小鼠模型中的肺成纤维细胞。为了更好地反映临床方案，IPF人肺成纤维细胞 （HLFS）将转移到C.B-17 SCID/BG小鼠中，以测试MPS在 肺纤维化。这些研究的成功将导致提交有关动物的II期SBIR研究 自发肺纤维化，药效/药代动力学分析，一项基于IND的FDA研究 未来临床药物发育减弱慢性肺纤维化。