Visiting Scientist - Nath Lab at Oklahoma Medical Research Foundation – Oklahoma City, Oklahoma

Position Overview and Responsibilities
Project: Functional Genomics of SLE Risk Variants in UBASH3A

Project Overview:
The Nath Lab is seeking a highly skilled Molecular Biologist with expertise in Bioinformatics to assist in the functional characterization of genetic variants associated with Systemic Lupus Erythematosus (SLE). While many autoimmune risk variants reside in distal enhancers, a significant subset of SLE risk is driven by splicing quantitative trait loci (sQTLs). In SLE, where T-cell hyperactivation is a hallmark, subtle shifts in splicing can lead to the loss of key regulatory proteins, effectively "removing the brakes" from the immune system. This project integrates state-of-the-art Large Language Models (LLMs) for genomics, such as AlphaGenome, with rigorous experimental validation, including minigene assays, to decode how non-coding variants drive T-cell hyperactivity.

The Mechanism: UBASH3A & rs1893592. Our research focuses on the UBASH3A locus, a negative regulator of T-cell receptor (TCR) signaling. We have identified a high-impact mechanism involving the rs1893592 haplotype:

• Splice Disruption: The risk allele disrupts a canonical donor site, forcing the use of a cryptic splice donor.
• mRNA Decay: This creates a premature stop codon, triggering Nonsense-Mediated Decay (NMD) and degrading the transcript.
• T-Cell Fallout: The resulting depletion of UBASH3A protein leaves T cells hyper-responsive to self-antigens, driving the pro-inflammatory SLE phenotype.

Technical Objectives The candidate will bridge computational predictions and physical proof using the RHCglo minigene pipeline:

• Design & Cloning: Engineer reporter constructs for the UBASH3A rs1893592 haplotype.
• Splice Mapping: Use minigene systems to confirm cryptic site activation.
• Quantification: Measure transcript ratios via RT-qPCR, ddPCR, and fragment analysis.
• Therapeutic Screening: Test Antisense Oligonucleotides (ASOs) to bypass the cryptic site and restore protein expression.

Why This Role is Essential
Computational prediction is a hypothesis; the minigene assay is the proof. The successful candidate will bridge this gap, providing the first definitive evidence that these variants are the primary drivers of T-cell dysfunction in lupus patients. This work establishes the foundational framework for moving from genetic association to precision therapeutic intervention.

Minimum Qualifications

• Ph.D. in a biological science, chemistry, physics or other relevant area, M.D., or equivalent.
• Collaboration with experimental and clinical scientists to address specific target mechanism questions with genomic insights is essential.
• This position demands a highly motivated, self-driven individual with excellent teamwork and organizational skills.
• Creativity, biological insight, and problem-solving skills in computational research.
• Must be detail-oriented, organized, and able to work independently, as well as part of a team.

OMRF Overview
Founded in 1946, the Oklahoma Medical Research Foundation (OMRF) is among the nation’s oldest, most respected independent, nonprofit biomedical research institutes. OMRF is dedicated to understanding and developing more effective treatments for human diseases, focusing on critical research areas such as Alzheimer’s disease, cancer, lupus, multiple sclerosis, and cardiovascular disease. OMRF follows an innovative cross-disciplinary approach to medical research and ranks among the nation’s leaders in patents per scientist.

Located in Oklahoma City, a city that offers a dynamic and flourishing downtown area, with low cost of living, short commute times and a diversified economy, OMRF has been voted one of the Top Workplaces since the inception of the award. This achievement has been accomplished thanks to OMRF individuals who share a unified understanding that our excellence can only be fully realized with a collective commitment to our mission, “. . . so that more may live longer, healthier lives.” Successful candidates will demonstrate commitment to this mission.

OMRF is an Equal Opportunity Employer.