This is a proposal to provide protected time for Dr. Drake to provide greater mentoring to junior clinical investigators as well as increase her capacity to expand her clinical investigations in interstitial lung disease. Dr. Drake proposes a mentoring plan which will facilitate the effective transition from junior clinical investigator to research scientist. She provides a detailed description of her own augmentation of further training in clinical trial implementation. Her current research projects are thematically linked through their focus on molecular and immunologic determinants of sarcoidosis clinical outcome for the purpose of identifying novel therapeutic interventions. In particular, her research focuses on the contribution of mycobacterial induction of T cell dysfunction to sarcoidosis disease progression, and the capacity of antimycobacterial therapy to restore T cell function. Trainees have been involved in many aspects of the ongoing patient-oriented research including study design, patient accrual, data collection, laboratory assays and analysis and presentation of findings. The transformative nature of the proposal is to investigate the safety of Nivolumab, an antibody against human Programmed Death-1, in patients with chronic pulmonary sarcoidosis. This investigation will allow the translation of molecular mechanisms identified at the bench to immune function within the host. The proof-of-concept data obtained from this K24 investigation will serve a pilot data for a Phase II clinical investigation of the efficacy of Nivolumab on a clinical endpoint associated with sarcoidosis mortality, absolute FVC.

Public Health Relevance

Sarcoidosis is a granulomatous disease of the lungs with increasing morbidity and mortality. Current therapeutic options demonstrate limited efficacy on factors associated with sarcoidosis mortality, such as forced vital capacity (FVC), making the necessity for novel therapies paramount. This proposal involves dedicated mentoring strategies of junior clinical investigators of interstitial lung diseases, as well as effective execution of clinical investigations that will lead to new therapeutic options for sarcoidosis patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
5K24HL127301-04
Application #
9452100
Study Section
NHLBI Mentored Patient-Oriented Research Review Committee (MPOR)
Program Officer
Kalantari, Roya
Project Start
2016-02-15
Project End
2021-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232
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Celada, Lindsay J; Kropski, Jonathan A; Herazo-Maya, Jose D et al. (2018) PD-1 up-regulation on CD4+ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-?1 production. Sci Transl Med 10:
Celada, Lindsay J; Rotsinger, Joseph E; Young, Anjuli et al. (2017) Programmed Death-1 Inhibition of Phosphatidylinositol 3-Kinase/AKT/Mechanistic Target of Rapamycin Signaling Impairs Sarcoidosis CD4+ T Cell Proliferation. Am J Respir Cell Mol Biol 56:74-82
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Carvalho, Evanir S; de Souza, Alexandre W S; Leão, Sylvia Cardoso et al. (2017) Absence of mycobacterial DNA in peripheral blood and artery specimens in patients with Takayasu arteritis. Clin Rheumatol 36:205-208
Moller, David R; Rybicki, Ben A; Hamzeh, Nabeel Y et al. (2017) Genetic, Immunologic, and Environmental Basis of Sarcoidosis. Ann Am Thorac Soc 14:S429-S436
Gelbard, Alexander; Katsantonis, Nicolas-George; Mizuta, Masanobu et al. (2016) Idiopathic subglottic stenosis is associated with activation of the inflammatory IL-17A/IL-23 axis. Laryngoscope 126:E356-E361
Celada, Lindsay J; Drake, Wonder P (2015) Targeting CD4(+) T cells for the treatment of sarcoidosis: a promising strategy? Immunotherapy 7:57-66