Background:
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease marked by progressive motor neuron loss. Emerging evidence suggests a critical, previously underappreciated role for skeletal muscle in ALS onset and progression, highlighting pathological and molecular interplay between brain and muscle. However, systematic, high-resolution molecular analyses across these tissues remain scarce. This project will use advanced wet-lab and computational techniques—including single-cell and bulk sequencing—to investigate conserved and tissue-specific molecular signatures in ALS-affected brain and muscle. Findings may uncover systemic drivers of ALS and identify novel therapeutic targets.
Aim:
To define conserved and tissue-specific molecular perturbations in brain and muscle in ALS using multi-omic approaches at single-cell and bulk resolution.
Student Development:
The student will undertake a truly cross-disciplinary, multi-laboratory PhD that integrates the fields of muscle biology, neurobiology, and neurology. This program will provide training in both advanced wet-lab techniques and computational methodologies, fostering expertise in molecular and systems-level analyses. The student will acquire hands-on experience in isolating, purifying, and preparing key biomolecules for high-throughput sequencing in both whole tissue and single-cell samples. This will be complemented by training in computational biology. Development in non-technical skills, for example scientific communication, manuscript preparation, will also be targeted.
Milestones:
• Year 1: Establish mouse colonies; collect brain and muscle tissues at defined disease stages; isolate single-cell/nuclei; pilot single-cell/bulk sequencing; develop computational skills for handling and pre-processing of data.
• Year 2: Generate full-scale datasets; conduct cell-type-specific analyses and data integration.
• Year 3: Identify conserved and specific ALS perturbations; validate key targets; begin human sample analyses.
• Year 4: Finalise integrative analyses; prepare thesis/publications; present findings.
Rotation Project:
The student will analyse single-cell co-assayed RNA+methylome data from ALS muscle to identify epigenomic and transcriptomic defects across muscle subtypes. Analyses will include clustering, subtyping, differential expression, and pathway enrichment, informing the broader PhD project.