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Funded Research

Laboratory concept; Scientist uses a dropper to transfer chemical reagent to test tube. He observes the chemical reaction with a blurred background of research in the laboratory

NAAF’s research program funds investigations that advance the understanding of the mechanisms behind alopecia areata, help identify new therapeutic targets, provide information on the biological, psychosocial, and economic impacts, and further knowledge toward treatments and a cure. Since 1985, NAAF has awarded more than 208 research grants totaling more than $5.7 million. The studies we’ve invested in have enabled significant advances in research by helping to unravel the genetics of alopecia areata, identify important immune pathways, and yield clues to targeted treatments.

Find out about applying for a grant on the Research Grants and Awards page.

High dimensional characterization of the systemic immune profile of pediatric alopecia areata

Year: 2023 PI Name: Benjamin Ungar, MD Award Type: Pediatric AA Challenge Grant Status: In Progress Summary:
Alopecia areata (AA) is a common cause of non-scarring hair loss that affects around 2% of people worldwide. AA is known to be generally caused by the immune system attacking hair follicles, but many details of this process remain unknown. A few studies have suggested that the inflammation in AA is not restricted to the skin but involves systemic immune responses with measurable inflammatory markers in peripheral blood. However, the number of studies is limited and they have just evaluated AA adult patients. The objective of our proposal is to characterize the immune cell profile and circulating inflammatory biomarkers in blood from pediatric AA patients.

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Abstract:
Alopecia areata (AA) is an immune cell-mediated disease characterized by non-scarring hair loss with a 2.1% lifetime risk. The pathogenesis of AA remains incompletely understood, but a key role for T cells damaging the hair follicle is well-established. Recent studies have also demonstrated that AA is not skin-limited; AA is characterized by activated CD4+ and CD8+ T cell subsets in peripheral blood, with corresponding inflammatory biomarkers substantially elevated in serum samples. However, this evidence is restricted to T cell responses in adult AA patients without characterization of other immune cell components and data in pediatric AA subjects are lacking. Our goal, therefore, is to high-dimensionally describe systemic immune pathways involved in pediatric AA by characterizing peripheral innate and adaptive immune populations and their associated biomarkers. We plan to collect blood samples from pediatric subjects (12-18 years) with AA (n=30) and healthy controls (n=30). Phenotypical and functional characteristics of circulating immune cells will be established by spectral flow cytometry (~60 markers). Serum samples will be analyzed using Olink platform for the analysis of ~500 analytes. Circulating biomarkers will be evaluated and correlated with immune cell subsets and clinical severity (Severity of Alopecia Tool, SALT, scores). This proposal will expand our mechanistic understanding of pediatric AA, identifying potential therapeutic targets and paving the way for disease-modifying treatments.

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Impact: Improved understanding of the nuances of the systemic inflammatory process in alopecia areata is important to inform how current treatments should be applied as well as to identify new potential treatments.

Alopecia & Us: Studying the impact of alopecia areata to adolescents and the family

Year: 2023 PI Name: Chantal Cotter, MD Award Type: Pediatric AA Challenge Grant (cofunded with PeDRA) Status: In Progress Summary:
Alopecia areata (AA) is one of the most common hair loss disorders characterized by loss of hair in round patches, usually on the scalp. The exact cause of AA is unknown, but it seems to be caused by the immune system attacking the hair follicles by mistake. Having AA can have impact on a child’s sense of well-being and increase their risk of mental health disorders including depression, anxiety, and OCD. Further, there may an impact on the family’s quality of life. Understanding this burden is paramount to ensuring we understand the full effect AA has on a child. We will do this via an online questionnaire which patients (aged 12-18) and their families can complete at home, anytime, anywhere in the world and in any language. Only through awareness of the full impact of this disease we will be able to advocate for access to treatments but also campaign for recognition and support of mental health in this group.

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Abstract:
Patients with alopecia areata (AA) in the adolescent population have consistently demonstrated poor health related quality of life measures with disease severity and increasing age correlating with poorer quality-of-life scores. In addition, there is research to suggest that there is a high prevalence of psychosocial comorbidities in adolescent patients suffering from AA. We hope to establish a research platform for adolescent patients with AA allowing the phenotypic and in-depth, crosssectional epidemiological studying of the illness. We will also study mental wellbeing, including psychosocial comorbidities, disease perception and stigma. Further we will examine the effect of childhood AA on the family and capture the sequalae of disease on family life. We aim to recruit 1000 patients worldwide in this observational study. Adolescents and their parents will have the opportunity to participate through a self-reporting online platform. Patients will complete several concise e-questionnaire-based metrics, including the Children’s Dermatology Life Quality Index, the Pediatric Index of Emotional Distress, the Family Reported Outcome Measure, the Family Dermatology Life Quality Index and EQ-5DY. This study will enable future research into therapeutic responsiveness by linking treatment effectiveness with research into predictive parameters such as the psychological and socioeconomic status of the adolescent patient and family. Further we hope to highlight the importance of the psychological impact of AA in adolescents and their families prompting a more holistic approach of such patients.

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IL-15 as a Candidate Key Cytokine in Alopecia Areata Pathobiology

Year: 2020 PI Name: Ralf Paus, MD Award Type: Research Grant Status: Completed Summary:
The purpose of this project is to test the hypothesis that blockade of interleukin-15 (IL-15) or IL-15 receptor-alpha can provide therapeutic benefit in alopecia areata.

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Abstract:
Effective alopecia areata (AA) treatment requires selective targeting of the key pathomechanisms to combine optimal, long-lasting therapy outcomes with reduced adverse effects. Recent research has suggested that the multi-function cytokine, interleukin-15 (IL-15), is important in AA pathobiology. Yet, convincing evidence for this remains to be generated in the human system. Specifically, since collapse of the hair follicle’s (HF) physiological immune privilege (IP) is an essential prerequisite for AA lesions to develop while HF-IP restoration is required for hair regrowth, it is critical to clarify the impact of IL-15 on human HF-IP - either directly, or indirectly. Here, we propose to do this by asking (in optimally suited, perfectly complementary human ex vivo and in vivo assay systems, i.e. AA patient skin biopsies, scalp HF organ culture and the humanized AA mouse model) whether: a) IL-15 and/or IL-15 receptor-alpha expression in/around lesional and non-lesional AA HFs is abnormal compared to healthy human scalp skin; b) IL-15 alone induces and/or enhances IFNγ-induced human HF-IP collapse; c) selectively antagonizing IL-15 receptor-alpha mediated signaling prevents experimentally induced HF-IP collapse and/or even restores HF-IP and promotes human hair regrowth in vivo; d) IL-15 promotes IFNγ secretion by pathogenic T/NK cells and/or promotes pathological perifollicular mast cell/T cell interactions in vivo. These clinically highly relevant studies will clarify whether IL-15 signaling really deserves selective targeting in future AA management, which adverse HF effects this could exert, and whether there is subgroup of AA patients who likely will benefit most from this.

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Impact: If successful, this study could provide new insights into the mechanism of alopecia areata pathogenesis mediated by IL-15 with important implications for future therapeutic intervention.

Collective Mechanism of Hair Regrowth during Alopecia Areata Resolution

Year: 2020 PI Name: Maksim Plikus, PhD Award Type: Pilot & Feasibility Grant Status: Completed Summary:
This project aims to evaluate evidence that progression from telogen to anagen growth follows a wave pattern by repeated evaluation with optical coherence tomography imaging; and to perform single cell sequencing to identify factors that predict progression to anagen.

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Abstract:
In alopecia areata (AA), thousands of actively growing (anagen) scalp hair follicles transition into a dormant (telogen) state. When AA resolves, either spontaneously or in response to JAK inhibitor treatment, the newly formed anagen follicles re-emerge rapidly in what grossly appear to be spreading waves. This growth pattern is commonly seen in rodents, where spreading waves are the outcome of a collective behavior, when anagen follicles signal to activate neighboring telogen follicles to also enter anagen in a chain-like reaction. This mechanism leads to a highly efficient anagen activation across large regions of skin. Inspired by our preliminary data on hair regrowth patterns in JAK inhibitor-treated AA patients, in this pilot application we propose to definitively establish the existence of a wave-like mechanism for anagen activation in human scalp, using optical coherence tomography imaging coupled with histological analysis of re-growing wave-front in AA. We will also collect single-cell RNA-sequencing data from wave-front hair-bearing skin and compare its cellular composition and key molecular changes to those of adjacent alopecic areas. High throughput single-cell data will be used to develop hypotheses on cellular and signaling changes that accompany collective AA hair regrowth, previously undescribed in human hair. We will be able to identify hair regeneration-associated changes in intra- and peri-follicular cell types, including immune cells, and key inhibitory and activating signaling factor changes. The hypothesis proposed herein is novel for the AA field, and its results will significantly advance the understanding of AA resolution mechanisms and open new lines of AA research.

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Impact: If successful, this study could provide important mechanistic insights into hair biology, identify novel molecular targets for anagen activation, and lead to the development of new growth factor-based strategies for enhanced hair regeneration in patients with alopecia areata.

Nutraceutical Stimulation of Intrafollicular Autophagy as an Adjuvant Strategy in the Management of Alopecia Areata

Year: 2019 PI Name: Ralf Paus, MD Award Type: Pilot & Feasibility Grant Status: Completed Summary:
This project will explore whether alopecia areata hair follicles display malfunctions in autophagy, which may make them more susceptible to immune-mediated hair follicle damage, and whether promoting hair follicle autophagy with nutraceuticals enhances human hair follicle growth and stress-resistance.

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Abstract:
Although novel treatments for alopecia areata (AA) such as JAK inhibitors can be efficacious, they are extremely expensive, may have long-term adverse effects, and don’t prevent AA relapse after therapy is discontinued. Therefore, new supportive AA therapies remain to be developed that also aid more permanent hair regrowth. Autophagy is a organelle and protein recycling process used by cells to facilitate growth and survival during stress. Recently, we have demonstrated that human scalp hair follicles (HFs) recruit autophagy to sustain their growth, while blocking HF autophagy inhibits human hair growth, Therefore, we propose to explore whether AA HFs display malfunctions in autophagy, which may make them more susceptible to immune-mediated HF damage, and whether promoting HF autophagy with nutraceuticals enhances human HF growth and stress-resistance. Specifically, we will investigate whether the expression of autophagy marker proteins and autophagolysosomes differ between healthy, non-lesional and lesional AA HFs. Next, we study whether interferon- the key cytokine in AA pathogenesis, modulates autophagy (i.e. LC3B and SQSTM1 expression and autophagolysosome generation) and whether inhibiting autophagy by LC3B gene-silencing prevents or promotes interferon-induced damage in organ-cultured human HFs. Finally, we will investigate whether enhancing autophagy by recognized enhancers of autophagic flux, i.e. the nutritional supplements caffeine and/or methylspermidine, makes cultured human HFs more resistant to interferon-induced HF damage and growth inhibition. These important pilot data will systematically introduce autophagy into translational AA research and is expected to identify a novel supportive therapeutic strategy in future AA management by nutraceuticals/cosmetics that targets autophagy.

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Impact: If successful, this study may help inform new treatment strategies in alopecia areata through the use commercially available nutraceuticals that target autophagy.

A Novel Treg Augmenting Therapy For Patients With Alopecia Areata

Year: 2019 PI Name: Michael D. Rosenblum, MD Award Type: Research Grant Status: Completed Summary:
This project will examine the function of regulatory T cells (Tregs) in the activation and differentiation of hair follicle stem cells in alopecia areata and determine whether the activity of Tregs can be modulated in alopecia areata using a novel IL-2 molecule.

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Abstract:
Regulatory T cells (Tregs) play a major role in establishing and maintaining immune homeostasis. We have discovered that both murine and human skin contain a unique population of Tregs that preferentially localize to hair follicles (HFs) and that these cells are required for HF regeneration as well as proper HF cycling. In addition, we have found that Tregs mediate these effects by promoting the activation and differentiation of hair follicle stem cells (HFSCs). The underlying theme of this proposal is to provide the cellular and molecular foundation for Treg augmentation therapy to treat patients with alopecia areata (AA). To achieve this goal, we will assess whether augmenting Tregs in mice results in enhanced HFSC function and HF cycling/regeneration. In addition, using cutting-edge CyTOF technology, we will comprehensively quantify the immune cell subsets infiltrating AA skin. In final experiments, we will attempt to augment Tregs in single cell suspensions derived from lesional AA skin and Treg activation quantified relative to other immune cell subsets. Given that AA is defined by both a dysfunction in HF regeneration and a defect in Tregs, our results may have direct implications for patients suffering from this disease.

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Impact: If successful, this study may help pave the way for future clinical trials testing the safety and efficacy of regulatory T cell (Treg) augmenting therapies in patients with alopecia areata.

Role Of Autophagy In Alopecia Areata

Year: 2019 PI Name: Rupali Gund, PhD Award Type: Mentored Investigator Award Status: Completed Summary:
This project aims to understand the role of autophagy (a normal physiological process in the body that deals with destruction of cells in the body) in normal hair cycling and its role in the development of alopecia areata in the C3H/HeJ mouse model.

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Abstract:
Alopecia Areata (AA) is an organ-restricted autoimmune disease that specifically attacks the hair follicles, resulting in well-demarcated (AA Patchy) or diffuse non-scarring hair loss of the scalp (AA Totalis) or the entire body (AA Universalis). AA is a highly prevalent disease with a lifetime risk of 2.1%, however, the underlying disease mechanisms remain incompletely defined and under-studied. Histologically, AA presents as a “swarm of bees” in which inflammatory T lymphocytes attack the pigmented actively growing hair follicles. The prevalent notion for disease is thought to be the loss of immune privilege of hair follicles causing abnormal activation of pathogenic T cells. Genetic association studies previously conducted in our lab found several autophagy related genes associated with AA. In addition, our gene expression analysis revealed altered expression of autophagy related genes, prompting us to hypothesize that dysregulation of autophagy plays a critical role in AA pathogenesis. Autophagy is a survivalpromoting mechanism that involves capturing, degradation, and recycling of intracellular proteins and organelles in lysosomes. However, the contribution of autophagy in loss of hair follicle immune privilege and development of AA is not characterized. This project aims to understand the role of autophagy in normal hair cycling and its contribution to the development of alopecia in grafted C3H/HeJ mouse model.

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Impact: If successful, this study could provide new insights into the mechanism of alopecia areata pathogenesis mediated by autophagy and also identify novel targets for therapeutic intervention.