Sarcoidosis and Alpha-1 Antitrypsin Deficiency are uncommon, understudied diseases that lack safe, effective treatments. Sarcoidosis is a multisystem granulomatous disorder that involves the lungs in over 90% of affected individuals and may cause end-stage pulmonary fibrosis and death. With an incidence of ~10-40 per 100,000 people in the U.S., sarcoidosis represents a significant health problem and health disparity concern. The pathologic hallmarks of sarcoidosis are non-caseating granulomas and polarized Th1 immunity at sites of disease. There is tremendous clinical heterogeneity with respect to organ involvement, severity and clinical course with both remitting and chronic progressive disease. There are no diagnostic tests for sarcoidosis except for biopsy of affected tissues, and no clinically useful biomarkers for risk stratification, prognosis or response to treatment. The goals of the study are to identify molecular abnormalities and their relationship to disease characteristics by employing genomics and microbiomics analyses of systematically phenotyped subjects, and to elucidate pathogenic mechanisms and identify predictors of disease. Proposed Aim 1 studies will systematically phenotype newly diagnosed sarcoidosis patients and provide lung, blood and tissue samples for study wide genomic and microbiomic analyses. Study-wide protocols will be established to evaluate the antigen specific immune responses to candidate pathogenic microbial antigens in sarcoidosis and correlate these dynamic measures with clinical phenotype and genomic/microbiomic analyses. Proposed Aim 2 studies will explore the hypothesis that serum amyloid A, an acute phase reactant and amyloid precursor protein, is a central mediator of chronic inflammation and fibrosis by correlating SAA levels in blood, lung and tissues with clinical phenotype and genomic/microbiomic analyses, assessing the proinflammatory and profibrotic cytokine-inducing effects of SAA on blood and lung cells in sarcoidosis, and identifying the receptor pathways that mediate these effects. These studies may establish links between specific clinical phenotypes, microbial etiologies, and common pathogenic mechanisms to provide a framework for new therapeutic approaches to sarcoidosis.

Public Health Relevance

Sarcoidosis is a disorder characterized by inflammatory nodules called granulomas that can involve any part of the body. The cause of sarcoidosis is uncertain, the diagnosis is difficult, and there are no safe, effective treatments. These studies will examine whether specific clinical features correlate with gene expression, microbial exposures or unbalanced immune responses to microbial proteins to potentially identify new targets for treatment of this disease.

Agency
National Institute of Health (NIH)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HL112708-03
Application #
8662311
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Punturieri, Antonello
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21218