A5028025625- Protease and Inhibitor Mechanisms
- Neonatal Respiratory Health Research
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Cell Adhesion Molecules Research
- Blood Coagulation and Thrombosis Mechanisms
- Peptidase Inhibition and Analysis
- Chronic Obstructive Pulmonary Disease (COPD) Research
- Immunotherapy and Immune Responses
- Congenital Diaphragmatic Hernia Studies
- Connective tissue disorders research
- Tissue Engineering and Regenerative Medicine
- T-cell and B-cell Immunology
- Inhalation and Respiratory Drug Delivery
- Immune Response and Inflammation
- Asthma and respiratory diseases
- Cancer Cells and Metastasis
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Medical Imaging and Pathology Studies
- Immune cells in cancer
- Signaling Pathways in Disease
- Cancer, Hypoxia, and Metabolism
- Cellular transport and secretion
- Pancreatic and Hepatic Oncology Research
- Lysosomal Storage Disorders Research
- Neuroendocrine Tumor Research Advances
Pulmonary and Allergy Associates
2024
University of California, San Francisco
2014-2023
Cardiovascular Institute Hospital
2011-2021
University of California System
2014-2021
University of California San Francisco Medical Center
2019
Chapman University
2015
Pulmonary and Critical Care Associates
2012-2013
Exelixis (United States)
2012
Pfizer (United States)
2012
Brigham and Women's Hospital
1995-2006
Mechanisms leading to fibroblast accumulation during pulmonary fibrogenesis remain unclear. Although there is in vitro evidence of lung alveolar epithelial-to-mesenchymal transition (EMT), whether EMT occurs within the currently unknown. Biopsies from fibrotic human lungs demonstrate epithelial cells with mesenchymal features, suggesting EMT. To more definitively test capacity for EMT, mice expressing beta-galactosidase (beta-gal) exclusively were generated, and their fates followed an...
Pycnodysostosis, an autosomal recessive osteochondrodysplasia characterized by osteosclerosis and short stature, maps to chromosome 1q21. Cathepsin K, a cysteine protease gene that is highly expressed in osteoclasts, localized the pycnodysostosis region. Nonsense, missense, stop codon mutations encoding cathepsin K were identified patients. Transient expression of complementary DNA containing mutation resulted messenger RNA but no immunologically detectable protein. Thus, results from...
Integrin function is central to inflammation, immunity, and tumor progression. The urokinase-type plasminogen activator receptor (uPAR) integrins formed stable complexes that both inhibited native integrin adhesive promoted adhesion vitronectin via a ligand binding site on uPAR. Interaction of soluble uPAR with the active conformer mimicked inhibitory effects membrane Both uPAR-mediated altered were blocked by peptide bound disrupted complexes. These data provide paradigm for regulation in...
Formation of the atherosclerotic intima must involve altered metabolism elastin-rich arterial extracellular matrix. Proteases potentially involved in these processes remain unclear. This study examined expression potent elastases cathepsins S and K human atheroma. Normal arteries contained little or no cathepsin S. In contrast, macrophages atheroma abundant immunoreactive Intimal smooth muscle cells (SMC), especially appearing to traverse internal elastic laminae, also enzymes. Extracts...
Cigarette smoke exposure is the major cause of chronic obstructive pulmonary disease (COPD). However, only a minority smokers develop significant COPD, and patients with asthma or asthma-like airway hyperresponsiveness eosinophilia experience accelerated loss lung function after cigarette exposure. Pulmonary inflammation characteristic feature lungs from COPD. Surprisingly, mediators this their contributions to pathogenesis varied natural history COPD are not well defined. Here we show that...
Urokinase receptors, expressed on surfaces of many cell types, focus to the pericellular space plasminogen-dependent proteolysis important in matrix remodeling and movement. We now report that urokinase receptor (uPAR) is also a high affinity (Kd < 30 nM) for vitronectin. Recombinant uPAR binds vitronectin absence urokinase, but binding promoted by concurrent either or fragments thereof containing its domain. Stable epithelial transfectants expressing membrane-anchored uPAR, not cells...
Abstract The cell type specific sequences of transcriptional programs during lung regeneration have remained elusive. Using time-series single RNA-seq the bleomycin injury model, we resolved dynamics for 28 types. Trajectory modeling together with lineage tracing revealed that airway and alveolar stem cells converge on a unique Krt8 + transitional state regeneration. These squamous morphology, feature p53 NFkB activation display features cellular senescence. Krt8+ appears in several...
The pathogenesis of atherosclerosis and abdominal aortic aneurysm involves breakdown the elastic laminae. Elastolytic cysteine proteases, including cathepsins S K, are overexpressed at sites arterial elastin damage, but whether endogenous local inhibitors counterbalance these proteases is unknown. We show here that, whereas cystatin C normally expressed in vascular wall smooth muscle cells (SMCs), this protease inhibitor severely reduced both atherosclerotic aneurysmal lesions. Furthermore,...
Laminins and their integrin receptors are implicated in epithelial cell differentiation progenitor maintenance. We report here that a previously unrecognized subpopulation of mouse alveolar cells (AECs) expressing the laminin receptor α6β4, but little or no pro-surfactant C (pro-SPC), is endowed with regenerative potential. Ex vivo, this expanded clonally as progenitors also differentiated toward mature types. Integrin β4 itself was not required for AEC proliferation differentiation. An vivo...
The assembly of signaling molecules surrounding the integrin family adhesion receptors remains poorly understood. Recently, membrane protein caveolin was found in complexes with β1 integrins. Caveolin binds cholesterol and several potentially linked to function, e.g., Src kinases, although has not been directly implicated integrin-dependent adhesion. Here we report that depletion by antisense methodology kidney 293 cells disrupts association kinases integrins resulting loss focal sites,...
Severe alpha-1-antitrypsin deficiency is the only proven genetic risk factor for chronic obstructive pulmonary disease (COPD). We have assembled a cohort of 44 probands with severe, early-onset COPD, who do not severe deficiency. A surprisingly high prevalence females (79.6%) was found. Assessment to relatives these COPD airflow obstruction and bronchitis performed determine whether significant familial aggregation independent deficiency, could be demonstrated. First- degree had...
Pulmonary fibrosis, in particular idiopathic pulmonary fibrosis (IPF), results from aberrant wound healing and scarification. One population of fibroblasts involved the fibrotic process is thought to originate lung epithelial cells via epithelial-mesenchymal transition (EMT). Indeed, alveolar (AECs) undergo EMT vivo during experimental ex response TGF-β1. As ECM critically regulates AEC responses TGF-β1, we explored role prominent integrin α3β1 by generating mice with cell–specific loss α3...
Abstract Invasion and metastasis increase after the inhibition of VEGF signaling in some preclinical tumor models. In present study we asked whether selective is sufficient to invasion c-Met block this effect. Treatment pancreatic neuroendocrine tumors RIP-Tag2 mice with a neutralizing anti-VEGF antibody reduced burden but increased hypoxia, hypoxia-inducible factor-1α, activation also metastasis. However, were by concurrent PF-04217903 or PF-02341066 (crizotinib). A similar benefit was...
Tumor killing by activated macrophages is not a highly determined biologic event, but relative capability influenced the local environment. An intrinsic macrophage cytotoxic effector system modulated serum and other environmental factors that can either enhance or suppress tumor killing. Activated kill cells only when regulating threshold drops to critically low level.
Abstract Tumor extracellular matrix has been associated with drug resistance and immune suppression. Here, proteomic RNA profiling reveal increased collagen levels in lung tumors resistant to PD-1/PD-L1 blockade. Additionally, elevated correlates decreased total CD8 + T cells exhausted cell subpopulations murine human tumors. Collagen-induced exhaustion occurs through the receptor LAIR1, which is upregulated following CD18 interaction collagen, induces SHP-1. Reduction tumor deposition LOXL2...