Rubin Lab | HSCRB

Rubin Lab Research

Summary

Our laboratory is broadly interested in the mechanisms underlying changes in the nervous system that occur because of aging or disease, as well as the interactions between the nervous system and the rest of the body. Studies involve a variety of in vivo, in vitro, and in silico approaches to generate insights into the complex molecular pathways that drive different disease states with a goal of identifying novel therapeutic insights. Current efforts in the lab include studies of the aging brain, CNS disorders (including neuromuscular and neurodegenerative) and skeletal muscle disorders.

Areas of Investigation

Aging of the Brain

Aging is the biggest risk factor for developing late-onset neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease. We are interested in identifying and studying the common biochemical changes that underlie aging and neurodegeneration.

More about this work

In previous work by our lab and others, we identified circulating factors that regulate CNS function in old mouse brains (Katsimpardi et al. 2014; Ozek et al. 2018). These studies utilized, in part, a surgical technique called heterochronic parabiosis, in which two animals, one old and one young, are surgically conjoined. The infusion of young blood into old mice stimulates the repair or rejuvenation of multiple tissues, most particularly the brain. To understand how this occurs we carried out large-scale single cell RNA sequencing studies to quantify the gene expression changes that occur in all of the major cell types in the brain (Ximerakis et al. 2019, 2023). This unique dataset uncovered genes and pathways that are associated with aging, reversed in parabiosis, and are viable candidates for potential treatments. We are particularly focused on changes in brain endothelial cells as reduction in both the quantity and quality of brain vasculature is observed in both aging and AD. Furthermore, vasculature regulates the passage of blood-borne factors into the brain and is itself a source of neuroactive factors. Our approach to studying vascular changes includes transgenic mouse models of AD and primary and iPSC-derived vascular cell cultures.

Skeletal Muscle

Neuromuscular disorders, such as Spinal Muscular Atrophy (SMA), often involve direct skeletal muscle defects in addition to the more well-studied spinal cord neuron degeneration. For example, SMA patients present with widespread muscle atrophy and weakness. Skeletal muscle tissue is known to regenerate rather well, a capability that is attributed to the activity of satellite cells, the resident skeletal muscle stem cell. We are carrying out studies to evaluate if defects in satellite cells contribute to neuromuscular disease. Our research combines the use of patient-derived iPSCs, genetic mouse models, and phenotypic drug screening methods.

More about this work

We are also exploring techniques to mobilize resident satellite cells or provide them as part of a cell therapy regimen in order to treat degenerative muscle diseases which are characterized by reduced muscle function due to atrophy, fibrosis and increased fat infiltration. Severe muscle damage can result in a less efficient regenerative process. For this work, we also use a combination of human and mouse in vivo and in vitro studies to carry out chemical screening and transcriptional profiling analyses to evaluate potential therapeutics related to targeting satellite cells.

Small Molecule Screening Assays

We have established an extensive range of complex, image-based assays to probe the properties of stem cells and cells derived from them. We use automated, high-content screening imagers, associated robotic equipment, and selected small molecule libraries and combine this high throughput approach with detailed molecular studies to further our understanding of the mechanisms of disease and determine which compounds are most likely to be of therapeutic value.

Join the Rubin Lab

Several postdoctoral positions are now available in the Rubin and Arlotta labs as part of an exciting new and broad multiomics program focused on brain aging.