Farooq Syed, Ph.D.

The overarching research objective of Dr. Syed's lab is to investigate the intricate crosstalk between pancreatic beta cells and immune cells in the development of type 1 diabetes (T1D). Specifically, the lab focuses on how intrinsic stress pathways within beta cells influence their interaction with immune cells during disease progression. This research explores how inflammation-driven dysregulation affects the epigenome (DNA and RNA modifications), RNA transcription and translational machinery in pancreatic islets and immune cells. To address these questions, the lab has developed several novel in vitro and in vivo animal models that closely recapitulate human T1D. The lab aims to uncover novel mechanisms and therapeutic targets contributing to T1D pathogenesis by understanding these molecular disruptions.

Research Highlights
 

Project 1: The Role of the β-Cell-Intrinsic Stress Pathways in T1D Pathogenesis

Type 1 diabetes (T1D) is an autoimmune disease marked by the progressive loss of insulin-producing β cells in the pancreas, resulting in insulin deficiency and dangerously elevated blood glucose levels. While the exact molecular mechanisms driving T1D remain unclear, clinical and preclinical studies implicate inflammatory proteins, particularly cytokines, in disease progression. Our recent findings demonstrate that inflammation activates specific signaling pathways within β cells, creating a feed-forward cycle of inflammation and cellular stress. This, in turn, increases the likelihood that β cells will be recognized and targeted for destruction by the immune system.

In this project, we investigate the role of β-cell integrated stress response (ISR) in mediating dysregulated mRNA translation and its impact on β-cell function and survival. To determine this, we are leveraging state-of-the-art multi-omics approaches (including epigenomics, transcriptomics and translatomics) to investigate how inflammation alters the RNA and protein profiles of human β cells. Additionally, we will utilize small-molecule inhibitors targeting specific stress-response pathways to better understand the role of inflammatory signaling in T1D development.

Project 2: Age-Related Pancreatic β-Cell Diversity in T1D
 

Evidence from human epidemiology and clinical studies suggests that age is a critical factor influencing disease-associated heterogeneity in type 1 diabetes (T1D). The overarching objective of this project is to identify cellular phenotypes in the pancreas that explain age-related differences in metabolic outcomes among individuals with T1D. In collaboration with Dr. Carmella Evans-Molina's group at Indiana University School of Medicine and Dr. Mark Atkinson's group at the University of Florida, we employ leading-edge single-cell and spatial transcriptomics approaches to analyze intact human pancreatic tissue. This work aims to uncover molecular mechanisms that may explain why β cells in younger individuals lose function more rapidly than those in adults.

Project 3: Role of Non-Coding RNAs in β-Cell Function and Survival in T1D
 

Non-coding RNAs, including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), play critical roles in regulating gene expression and cellular function. In pancreatic beta cells, these non-coding RNAs have emerged as key regulators of normal cellular function and survival under stress. This project focuses on understanding how these molecules modulate the response of β cells to immune-mediated inflammation, a hallmark of type 1 diabetes (T1D). By regulating pathways involved in insulin production, cellular stress responses, and inflammation, lncRNAs and miRNAs can influence β-cell fate, including their susceptibility to immune-mediated destruction. To elucidate the role of these non-coding RNAs in T1D, we employ targeted genetic and molecular approaches to identify novel therapeutic targets that could preserve β-cell function and prevent or delay T1D onset.

Project 4: Biomarkers
 

Early disease detection and timely therapeutic efficacy assessment through biomarker identification is crucial for personalized treatment approaches. In autoimmune diseases like type 1 diabetes (T1D), identifying biomarkers before the onset of clinical symptoms can significantly improve prevention strategies and guide therapeutic interventions. This project focuses on identifying cell-specific early biomarkers of T1D by investigating circulating nucleic acids and protein signatures derived from both β cells and immune cells. These studies are conducted using in vitro and in vivo model systems and liquid biopsy samples from individuals with and without T1D. The research particularly emphasizes the role of extracellular vesicles (EVs) and non-EV fractions as carriers of these disease-specific molecular signatures.