2024 Pediatric Lupus Research Grant Awardees

Hajera Amatullah, PhD, MPH 

University of Pennsylvania 

Title of Project 

Epigenetic Regulation of Myeloid Cells in Lupus 

Project Summary 

Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease driven by both genetic susceptibility and environmental risk factors. Epigenetic processes, which lie at the intersection of gene-environment interactions, play an important role in regulating immune gene expression and function. Myeloid cells (monocytes, macrophages and neutrophils) are sentinel innate immune cells that respond to diverse environmental signals with specific and timely execution of gene programs. Individuals with SLE have an expansion of myeloid cell populations which produce high levels of type I interferon. Epigenetic mechanisms in myeloid cells play a critical role in regulating pro-inflammatory and resolution gene programs to maintain homeostasis. 

Disruption of these epigenetic mechanisms lead to aberrant gene expression programs. Breakthrough therapeutic strategies targeting epigenetic proteins are currently in clinical trials for several cancers; however, the role and therapeutic application of targeting epigenetic proteins in chronic immune diseases such as SLE remain to be determined. Genome-wide association studies have recently identified an epigenetic protein (lysine demethylase 4C, KDM4C) that has disease risk variants associated with SLE. 

Our proposed work will evaluate: 

1. The functional role of this epigenetic protein in myeloid cells 
2. The molecular mechanism by which it controls inflammatory gene programs 
3. How KDM4C function is disrupted in SLE

Our work aims to provide evidence of epigenetic dysregulation in myeloid cells as contributors of SLE pathology and shed light on potentially novel targets for therapeutic strategies. 

Liyoung Kim, MD 

Boston Children’s Hospital 

Title of Project 

Immune pathway-specific genetic burden in childhood-onset lupus 

Project Summary 

Children with lupus tend to experience more severe illness and greater organ damage, particularly affecting their kidneys, heart, lungs, and brain. Genetics has been recognized as an important risk factor for childhood-onset systemic lupus erythematosus (cSLE). It is suspected that children with lupus have an amplifying genetic burden that contributes to the development of SLE at an earlier age. However, the various types of genetic burdens that lead to the spectrum of disease seen in cSLE have yet to be fully characterized. We suspect that different genetic burdens may result in distinct groups of symptoms and disease courses within cSLE. 

In this project, we will utilize a methodology known as pathway-specific polygenic risk scores (psPRS) to categorize genetic burdens that result in distinct groups of symptoms within cSLE. psPRS is an advanced combination of statistical and functional genomic methods used to measure genetic burdens. Compared to traditional PRS, psPRS also takes into account biological information related to the disease and has never been used for cSLE. Understanding the association between genetic burden and disease course in cSLE will lay the foundation for the use of human genomics to predict treatment responses and to understand the complex mechanisms that lead to the wide range of symptoms seen in patients with the same diagnosis. This will be a crucial step towards providing precision treatment for children with cSLE.