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Our group is broadly interested in translational research of rare lung diseases, which allows us to approach disease pathogenesis from the vantage point of a known molecular defect. Our goal is to develop new biomarkers and therapies with the potential
to favorably impact human health in a short time frame. Many of our laboratory directions have been inspired by patients we have met, which gives our work purpose and meaning, and motivates us to ask questions that matter.
The McCormack laboratory is interested in genetic interstitial lung diseases and pulmonary innate immunity. Current projects are focused on lymphangioleiomyomatosis (LAM), pulmonary alveolar microlithiasis (PAM) and the role of the alveolar epithelium
in influenza, mycobacterial and bacterial infection. We use animal models to develop biomarkers and strategies for trials, and try to focus on experimental plans that have a human trial on the horizon. As an example, we developed the PAM mouse model
by deleting the phosphate transporter, Npt2b, from the alveolar epithelium, as mutations in that protein are known to cause the disease in humans. The animals develop diffuse pulmonary alveolar microliths, which produce hyperdense infiltrates on radiographs
and C/T scans that are easily measured and quantified. The cytokine MCP-1 is elevated in the lungs of the PAM animals, and also appears in their serum. We also found that the very large alveolar protein, surfactant protein D (SP-D), was elevated in
PAM mouse serum, suggestive of lung injury and barrier dysfunction. We contacted a dozen PAM patients around the world to obtain blood, and found that MCP-1 and SP-D are also elevated in the serum of patients, and are now developing them as promising
biomarkers for disease progression and response to therapy. We found that stones isolated from the lungs of the PAM mice readily dissolve in calcium chelators such as EGTA and EDTA, suggesting therapeutic chelation lavage as a treatment approach;
an idea we intend to test in monkeys and bring to the bedside if proven safe. We have also found that a low phosphate diet reduces the stone burden in the lung, suggesting that a simple dietary intervention (perhaps together with a phosphate binder)
could be developed as a treatment. Our lab is actively trying to understand the mechanism of stone clearance due to phosphate restriction, focusing on the effect of phosphate hormone mediators such as VitD3 and FGF-23 on expression of alternative
phosphate transporters in the alveolar epithelium. We intend to conduct a trial in PAM patients through the NIH Rare Lung Disease Consortium, a network of 55 rare lung disease clinics located around the world, with Cincinnati as the hub, with co-investigators
Bruce Trapnell, MD, and Frank McCormack, MD. The RLDC conducted the MILES trial for LAM, which demonstrated that sirolimus is an effective treatment. On the basis of the MILES result, the FDA approved sirolimus for LAM in 2015, and over 40 percent
of LAM patients in North America are now taking the drug. Other past and present Cincinnati-based RLDC projects have included developing a pathologic classification system for the pediatric interstitial lung diseases, developing diagnostic tests for
pulmonary alveolar proteinosis, developing CT scanning as a biomarker of progression for alpha-1 antitrypsin deficiency, developing a longitudinal registry for LAM (MIDAS), and conducting a MILES-like trial of sirolimus in asymptomatic patients with
LAM who have normal lung function (the MILED trial). McCormack and Trapnell have also developed a collaborative UC/CCHMC program called the Translational Pulmonary Science Center, which organizes the resources necessary for translational research
in pulmonary disease and operates a CCTST-funded bronchoscopy core for the collection of lung samples.
Key accomplishments of the lab
1. Solution of the crystal structure of SP-A (with Barbara Seaton)2. Characterization of the structure and function relationship of surfactant proteins A (SP-A) and D (SP-D)3. Development of serum SP-A and VEGF-D as biomarkers in interstitial
lung disease4. Discovery of direct antimicrobial properties of SP-A and SP-D5. Elucidation of the role of the pulmonary epithelium in fibrogenesis (in Hermansky Pudlak mouse models)6. Identification of KGF as a promising therapeutic
strategy for therapy of bacterial and mycobacterial infections7. Elucidation of the molecular pathogenesis of pulmonary alveolar microlithiasis8. Development of biomarkers and therapeutic targets for pulmonary alveolar microlithiasis9. Discovery that the proliferative tone of alveolar type II epithelial cells determines susceptibility to influenza pneumonia
Publications resulting from our research
1. Multicenter Interventional LAM Early Disease Trial (MILED). Randomized controlled trial of early low dose sirolimus vs. placebo in LAM patients with
normal lung function
2. Multicenter International Durability of Sirolimus Trial (MIDAS).
Observational registry study of patients with LAM
1. Multicenter International LAM Efficacy of Sirolimus Trial (MILES).
Randomized controlled trial of sirolimus vs. placebo in LAM patients with abnormal lung function
2. Trial of an aromatase inhibitor in LAM (TRAIL). Randomized controlled trial of letrozole vs. placebo in post-menopausal patients with LAM
1. LAM patients interested in joining MIDAS, an observational registry, click here
2. PAM and LAM patient interested in joining a contact registry for information about upcoming trials, click here
Major projects in the lab
Potential projects for students and fellows:
Interests: Rare lung diseases; development of diagnostic, predictive and prognostic biomarkers; interrogating clinical samples to elucidate molecular pathophysiologies underlying pulmonary diseases; factors
that alter influenza susceptibility; differential diagnosis of lung diseases.
Potential projects: Clinical samples from patients with rare lung diseases have been collected. Investigator-initiated projects could be permitted with approval.
Research skills acquired: Clinical research design and implementation, laboratory methods, biostatistical analysis, molecular basis of disease.
Training required or time delay: Dependent upon project. For biomarker studies, sample procurement must be approved, fellow may need IRB training and approval.
U01HL131755 (McCormack, PI) 9/20/16-6/30/21NIH/NHLBIMulticenter Interventional Lymphangioleiomyomatosis Early Disease Trial (MILED)-CCCThe goal of this randomized clinical trial is to determine the effectiveness of low dose sirolimus
treatment in women with LAM who have preserved lung function. Role: Principal Investigator
R01HL127455 (McCormack, PI) 4/1/15-3/31/19NIH/NHLBIPathogenesis-Driven Therapeutic Development for Pulmonary Alveolar MicrolithiasisThe goal of this project is to develop a treatment for pulmonary alveolar microlithiasis
by doing trials in a mouse model that closely mimics human disease. Role: Principal Investigator
U54HL127672 (McCormack, Trapnell, co-PIs) 9/18/14-7/31/19NIH/NHLBIRLDC: Molecular Pathway-Driven Diagnostics & Therapeutics for Rare Lung Diseases.Goals: To
elucidate molecular pathways driving three rare lung diseases, lymphangioleiomyomatosis, pulmonary alveolar proteinosis, and Hermansky-Pudlak syndrome, and apply this knowledge towards the development of diagnostics and therapeutics. The goal of Project
1, Lymphangioleiomyomatosis, is to understanding the safety and efficacy of long-term sirolimus treatment through an observational study. Role: Administrative Director; Principal Investigator- Project 1
U01HL131022 (Henske) 11/1/16 - 10/31/19NIH/NHLBIThe Molecular and Genetic Pathogenesis of LAMThis U01 research collaboration is designed to understand the fundamental mechanisms leading to lymphangiogenesis
in LAM, with the goal of providing precision dosing for patients. Role: Co-Principal Investigator, Project 3
85120 Shriner’s of North America (McCormack, PI) 1/1/13-12/31/18Shriner’s of North AmericaKGF Modulation of Burn Induced Lung Injury and Infection #85120Goal: To determine if KGF plays an important role in
the pulmonary response to thermal injury in a murine model. Role: Principal Investigator
No number (McCormack, PI) 7/7/17-7/6/18Dept of Internal Medicine Distinguished Research Achievement Award Molecular Mechanisms of Osteoclastic Transformation of Alveolar MacrophagesWe will investigate
interventions such as low phosphate diet on osteoclast activity and microlith burden in a murine model of Pulmonary Alveolar Microlithiasis.Role: Principal Investigator
UH3TR000961 (N. Tony Eissa, PI) 6/18/13-8/31/17NIH/NCATSTherapeutic strategy for Lymphangioleiomyomatosis (LAM) and Tuberous SclerosisThe goal of this clinical Trial to test the effect of Src Kinase inhibitors
in patients with LAM. Role: Co-investigator
PR160175 (Madala, PI) 10/01/17-09/30/20DoD/USAMRAATherapeutic Benefit of Hsp90 Inhibition in Pulmonary FibrosisThe goal of this project is to generate new understanding of the factors
influencing IPF severity and mechanistically demonstrate how HSP90 activity contribute to the expansion of the fibrotic machinery in the pathology of IPF, and provide new therapies for clinical interventions for patients with IPF
R01 HL134801 (Madala, PI) 09/01/16-08/31/21NIH/NHLBIWT1 Regulation of Pulmonary FibrosisIdiopathic pulmonary fibrosis (IPF) is an incurable, disabling, and often fatal disease characterized by the distribution
of fibrotic lesions predominantly in the peripheral areas of the lung. Validation of the functional association between WT1-driven transcriptional programs and fibroblast phenotypes in the pathology of IPF, may provide new targets for clinical interventions
of IPF. Role: Co-Investigator
UL1TR001425 (J. Heubi, J. Tsevat, PIs) 8/14/15-3/31/19NIH/NCATSCincinnati Center for Clinical Translational Science and Training (CCTST)This is an NIH-supported CTSA to increase translational science discoveries
at the University of Cincinnati, Cincinnati Children’s Hospital Medical Center, and the Cincinnati Veterans Administrative Medical Center. Role: Co-Director, Pilot and Collaborative Translational and Clinical Studies (PCS)
T32HL007752 (J. Whitsett, F. McCormack and B. Trapnell; multiple PIs) 7/1/15-6/30/20NIH/NHLBILung and Cardiovascular Development and Disease Pathogenesis Training ProgramThe goal of this
training program is to train pre and postdoctoral fellows in molecular pathophysiology of heart, lung, and vascular disorders. Role: Co- Principal Investigator; mentor
R21HL133539 (Madala, PI) 7/5/16 – 6/30/18NIH/NHLBIIntegrative analysis of multi-omics data to target fibroblast activation in IPFThe goals of this project are to interrogate existing informatics databases
to identify compounds that inhibit fibroblast activation in IPF. Role: Co-Investigator
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