The goal of this application is to define a translational platform of candidate biomarkers for Alopecia Areata (AA). AA is one of the most common autoimmune diseases, with a lifetime risk of approximately 2%, affecting 5.3 million individuals in the United States alone, including males and females of all ages and ethnic groups. Autoimmunity is acquired against the hair follicles in the skin, which causes hair loss associated with an accumulation of immune-response cells around the affected hair follicles. The prognosis of AA is unpredictable and currently there is no definitive treatment. The chronic nature of this disease profoundly impacts patients. A dearth of information about the underlying pathology has been the major obstacle in identifying effective treatments. In 2000, NIH/NIAMS funded the National Alopecia Areata for the registration and data collection of individuals with a confirmed diagnosis of AA and their family members. For the purpose of this Ancillary Studies application, we require both fresh tissue biopsies as well as freshly-collected blood samples from a subset of 60 subjects. Therefore, it is essential that this grant be carried out in parallel with the NAAR contract. We will develop a translational platform for AA by characterizing the genetic networks of two interacting tissues in the context of an autoimmune disease: cells of the immune system as well as the skin. Translational advances in AA will likely have broad impact in autoimmunity. Our recent GWAS study in AA unexpectedly revealed a number of risk loci shared by rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), SLE, MS and psoriasis (PS). The commonality with RA, T1D, and CeD is especially noteworthy in light of the shared pathogenic expression of NK ligands in the target organ of each of these three autoimmune diseases. Thus, pursuit of biomarker development in AA, by integrating signatures in the blood and the target organ, could accelerate candidate biomarker discovery for other related autoimmune states in which the target organ is not as accessible. Importantly, these studies will provide the basis for a translational platform in AA;to identify molecular drivers of AA subtypes enabling drug development to be appropriately targeted and monitored in this disease.
In this proposal, we will apply high-throughput, genomic characterization methods to identify AA transcriptional anomalies across two interacting tissues, the scalp skin and T cells, for the first time. This project will generate genome-wide gene expression and miRNA profiles of T-cells in circulation as well as the accompanying gene expression profile of the skin itself. We will then integrate this analysis with our GWAS findings, together with serum cytokine measurements and semi-quantitative methods such as qPCR and IHC. These putative biomarkers may identify molecular subtypes of AA and shed light on novel therapeutic pathways for intervention in AA. Importantly, they provide the basis for a translational platform in AA that is a crucial element for development and monitoring of biologically-targeted clinical intervention trials.
|Pratt, C Herbert; King Jr, Lloyd E; Messenger, Andrew G et al. (2017) Alopecia areata. Nat Rev Dis Primers 3:17011|
|Mackay-Wiggan, Julian; Jabbari, Ali; Nguyen, Nhan et al. (2016) Oral ruxolitinib induces hair regrowth in patients with moderate-to-severe alopecia areata. JCI Insight 1:e89790|
|Harris, John E; Rashighi, Mehdi; Nguyen, Nhan et al. (2016) Rapid skin repigmentation on oral ruxolitinib in a patient with coexistent vitiligo and alopecia areata (AA). J Am Acad Dermatol 74:370-1|
|Chen, James C; Cerise, Jane E; Jabbari, Ali et al. (2015) Master regulators of infiltrate recruitment in autoimmune disease identified through network-based molecular deconvolution. Cell Syst 1:326-337|
|Jabbari, Ali; Dai, Zhenpeng; Xing, Luzhou et al. (2015) Reversal of Alopecia Areata Following Treatment With the JAK1/2 Inhibitor Baricitinib. EBioMedicine 2:351-5|
|Harel, Sivan; Higgins, Claire A; Cerise, Jane E et al. (2015) Pharmacologic inhibition of JAK-STAT signaling promotes hair growth. Sci Adv 1:e1500973|
|Xing, Luzhou; Dai, Zhenpeng; Jabbari, Ali et al. (2014) Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat Med 20:1043-9|
|Jabbari, Ali; Petukhova, Lynn; Cabral, Rita M et al. (2013) Genetic basis of alopecia areata: a roadmap for translational research. Dermatol Clin 31:109-17|