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 pulmonaryfibrosis, such as idiopathic pulmonary fibrosis (IPF). The disease exhibits a median survival time of only 3 to 5years 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 todemonstrate increased longevity in treated patients indicate the urgent need for new and better therapeuticagent(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 andFM transition phenomena, important pathogenic events associated with cancer malignancy, are primordially andmainly mediated by receptor-mediated tyrosine kinase (RTK) and PI3K-AKT signaling pathways. We have shownbefore the elevation of phospho-MARCKS in lung cancer tissues/cells associated with EM transition and the useof a peptide inhibitor, MPS (MARCKS PSD/ED Sequence), to suppress EM transition and lung cancermalignancy through tackling the aberrant MARCKS-PIP3 circuit associated with cancer pathogenesis. Theelevated phospho-MARCKS phenomenon is also seen in tissue sections and isolated fibroblasts derived fromIPF lungs, but not seen in any normal, non-fiberotic ones. Our recent publication had shown the therapeuticpotential of MPS peptide in the suppression of the fibrotic lesions in bleomycin-induced fibrotic mouse lungs. Invitro, MPS tackles the aberrant MARCKS-PIP3 circuit to suppress MARCKS phosphorylation and also selectivelyinhibits the EM/FM transition and myofibroblast fibrogenesis, as well as the alteration of M1/M2 macrophagepolarization. The selectivity occurs only on IPF-derived fibroblasts and activated macrophage, but not on thenormal and inactivated monocytes. Through peptide optimization, we have developed further a stable, morebiosafe, and high potency of a novel MPS-derived peptide, MPS-6413DTM. Initial studies have shown the efficacyof this peptide on the suppression of bleomycin-induced lung fibrotic lesions and deceased in mice, but not onthe control ones. We hypothesize that MPS-6413D is a potent anti-fibrotic lung drug on the inhibition of fibrogenicprogression of chronic lung fibrosis through tackling the MARCKS-PIP3 circuit. To test this hypothesis and thetherapeutic potential of this peptide, two aims are proposed. Aim 1 is to determine further the therapeutic effectsof MPS-6413D peptide on bleomycin induced lung fibrotic lesions in aged 32-week old (equivalent to 42 yearsold human) mice. The therapeutic potency will be determined on the inhibition of the expression of profibrogenicmarker 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 afterbleomycin exposure. Aim 2 is to evaluate an inhibitory effect of MPS-6413D peptide on fibrogenic activity of IPFlung 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 inlung fibrosis. Success of these studies will lead to the submission of the Phase II SBIR study on animals withspontaneous lung fibrosis, the pharmacodynamic/pharmacokinetic analysis, an IND-based study to FDA forfuture clinical drug development to attenuate chronic pulmonary fibrosis.
Public Health Relevance Statement: PROJECT NARRATIVE
Chronic pulmonary fibrosis, such as idiopathic pulmonary fibrosis, currently have no available
drugs for the treatment. We will test the therapeutic potency of a novel MPS-6413D peptide to
suppress chronic fibrotic mouse lungs.
Project Terms: Age ; ages ; Animals ; inhibitor/antagonist ; inhibitor ; Bleomycin ; Bleo ; Malignant Neoplasms ; Cancers ; Malignant Tumor ; malignancy ; neoplasm/cancer ; Felis catus ; Cats ; Cats Mammals ; Domestic Cats ; Feline Species ; Felis domestica ; Felis domesticus ; Felis sylvestris catus ; Cells ; Cell Body ; Collagen ; Diagnosis ; Disease ; Disorder ; Canis familiaris ; Canine Species ; Dogs ; Dogs Mammals ; canine ; domestic dog ; Pharmacotherapy ; Drug Therapy ; drug treatment ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Exhibits ; Extracellular Matrix ; Cell-Extracellular Matrix ; ECM ; Fibroblasts ; Future ; Growth ; Generalized Growth ; Tissue Growth ; ontogeny ; Human ; Modern Man ; In Vitro ; Longevity ; Length of Life ; life span ; lifespan ; Lung ; Lung Respiratory System ; pulmonary ; Lung diseases ; Pulmonary Diseases ; Pulmonary Disorder ; Respiratory Disease ; Respiratory System Disease ; Respiratory System Disorder ; disease of the lung ; disorder of the lung ; lung disorder ; macrophage ; MÏ ; monocyte ; Blood monocyte ; Marrow monocyte ; Mus ; Mice ; Mice Mammals ; Murine ; Legal patent ; Patents ; Patients ; Peptides ; Personal Satisfaction ; well-being ; wellbeing ; Drug Kinetics ; Pharmacokinetics ; Phosphorylation ; Protein Phosphorylation ; Protein Tyrosine Kinase ; EPH- and ELK-Related Tyrosine Kinase ; EPH-and ELK-Related Kinase ; Ephrin Type-A Receptor 8 ; Ephrin Type-A Receptor 8 Precursor ; Protein Tyrosine Kinase EEK ; Tyrosine Kinase ; Tyrosine-Protein Kinase Receptor EEK ; Tyrosine-Specific Protein Kinase ; Tyrosylprotein Kinase ; hydroxyaryl protein kinase ; tyrosyl protein kinase ; Publications ; Scientific Publication ; Pulmonary Fibrosis ; lung fibrosis ; Research ; RNA ; Non-Polyadenylated RNA ; RNA Gene Products ; Ribonucleic Acid ; Signal Transduction ; Cell Communication and Signaling ; Cell Signaling ; Intracellular Communication and Signaling ; Signal Transduction Systems ; Signaling ; biological signal transduction ; Testing ; Time ; Tissues ; Body Tissues ; indium-bleomycin ; In-bleomycin ; wortmannin ; Mediating ; Proto-Oncogene Proteins c-akt ; AKT ; Akt protein ; Protein Kinase B ; RAC-PK protein ; c-akt protein ; proto-oncogene protein RAC ; proto-oncogene protein akt ; rac protein kinase ; related to A and C-protein ; Injury ; injuries ; base ; Chronic ; Clinical ; Malignant - descriptor ; Malignant ; Phase ; Lesion ; Epithelial ; Myofibroblast ; Failure ; pulmonary function ; lung function ; Malignant neoplasm of lung ; Malignant Tumor of the Lung ; Pulmonary Cancer ; Pulmonary malignant Neoplasm ; lung cancer ; lung injury ; Lung damage ; Pirfenidone ; Therapeutic ; Therapeutic Agents ; Attenuated ; Inflammatory ; Deposit ; Deposition ; Adoptive Transfer ; ACAMP-81 ; MARCKS protein ; Myristoylated alanine-rich protein kinase C substrate ; PRKCSL ; myristoylated alanine-rich C kinase substrate ; protein kinase C substrate, 80-KD, light chain ; protein kinase substrate 80KD protein, light chain ; MARCKS gene ; Event ; Clinic ; System ; fibrogenesis ; Receptor Protein ; receptor ; success ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; novel ; Pathogenesis ; Lung Parenchyma ; Lung Tissue ; Structure of parenchyma of lung ; Pharmacodynamics ; Pathogenicity ; therapeutic testing ; therapeutic evaluation ; Clinical Drug Testing/Development ; Clinical Drug Development ; Mesenchymal ; in vivo ; AKT Signaling Pathway ; Phosphorylation Site ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Pathologic ; Process ; Therapeutic Effect ; injury and repair ; aged ; innovation ; innovate ; innovative ; peptidomimetics ; peptide mimetic ; peptide mimic ; drug testing ; drug detection ; mouse model ; murine model ; stem ; FDA approved ; protein biomarkers ; protein markers ; humanized mouse ; humanized mice ; clinical development ; idiopathic pulmonary fibrosis ; diffuse interstitial pulmonary fibrosis ;
