The Young-Pearse lab uses molecular approaches to study the functions of genes involved in neurodegenerative and neurodevelopmental diseases.

Tracy Young-Pearse's research group focuses on two main areas.

The identification of convergent cell and molecular pathways that lead to pathological mammalian brain development

New genetic findings in conjunction with stem cell models of human development provide an unprecedented opportunity to illuminate the cell and molecular bases of mental illness and developmental disorders. A major challenge to iPSC modeling of these disorders is that we are attempting to recapitulate subtle changes in subsets of cells in brain development and maturation. The challenge is compounded by the heterogeneity of both the clinical presentation and the genetic and environmental effectors of these diseases. Our approach is to focus on specific genetic disruptions individually, and then to compare genetic disruptions of similar clinical presentation, to look for points of convergence at the molecular and circuitry level.

Our first study involved genetically engineering (with TALENs and CRISPR/Cas) multiple mutations in hiPSCs in the gene DISC1. Through the analyses of multiple lines per genotype, over many wells of parallel differentiations, we have identified subtle but significant effects of DISC1 disruption in a subset of neural progenitor cells, which then manifest as modest molecular changes in mature neuronal cells.

While we complement these iPSC studies with in vivo rodent studies, it is important to study the development of our human cells in the context of an organized 3D structure. To this end, another area of interest for our lab is in the advancement of existing cerebral organoid technology along with xenotransplantation of human neural cells into lower species.

The identification of novel therapeutic targets for treating Alzheimer’s disease (AD)

As with our stem cell studies of neurodevelopmental disorders, we began iPSC modeling of AD with a focus on a single, strong genetic linkage - a fully penetrant missense mutation in the gene APP that causes an early-onset form of the disease. With these lines, we showed that this mutation altered the cleavage profile of APP to affect the types of Aβ secreted. We showed an important link between this altered Aβ, and the levels and phosphorylation state of tau. We used neurons from these lines to test two anti-Aβ immunotherapies, and were the first to show that APP mutant neurons responded to these treatment to rescue the tau phenotype.

While informative, these studies modeled one early-onset subtype of AD, and anti-Aβ immunotherapy may not be effective in neural cells from all AD patients. In order to identify novel targets for late-onset AD, we are interrogating two existing cohorts of aging humans followed longitudinally until death, after which time they donate brain tissue for extensive phenotyping. These cohorts have demonstrated what some clinicians and pathologists suspected, that AD is not a homogeneous disease. With our collaborators, we are using molecular, genetic, pathologic, and clinical data to identify networks containing putative targets for intervention. We are using our iPSC pipelines to integrate and test these newly identified targets in human neurons, astrocytes, and microglia.

We complement this human in vitro work with in vivo rodent studies to identify factors that regulate AD processes. Currently, we are interrogating the heterogeneity of late-onset AD observed in our cohort studies by examining human stem-cell derived neurons from the extreme ends of the pathological and clinical spectrum of AD. We then are using these cells to: 1) examine the responsiveness of neuronal cells derived from these subgroups to therapies directed against Aβ, and 2) determine the responsiveness of these subgroups to genetic modulation of putative AD-relevant networks that we have identified in our ongoing work.

Biosketch

Tracy Young-Pearse, co-leader of the HSCI Nervous System Diseases Program, is an Associate Professor in the Ann Romney Center for Neurologic Diseases at Brigham and Women’s Hospital and Harvard Medical School in the Department of Neurology. She received her undergraduate degree from Skidmore College in her hometown of Saratoga Springs, NY.  She then went on to enter the Biomedical and Biological Sciences (BBS) program at Harvard Medical School, where she received her Ph.D. in Genetics in the lab of Connie Cepko. She then completed a postdoctoral fellowship under the mentorship of Dennis Selkoe before starting her own lab in 2010