FXTAS Key Molecular Pathways Converge with Other Neurodegenerative Disorders

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PROJECT SUMMARY/ABSTRACT THE CANDIDATE. Dr. Lozano is an early career physician-scientist, who has drawn on his academic achievement and diverse training in clinical and basic science to develop an independent research program. Through his work, he has developed laboratory skills in genetics and molecular biology, as well as clinical research which together form the foundations of this ongoing project. CAREER DEVELOPMENT. Dr. Lozano's overall long-term career goal is to lead a meaningful and sustainable research program that will allow him to remain a well-established and independent investigator in the area of Fragile X-related disorders. These goals will be accomplished through intense mentorship (Drs. Alison Goate (mentor), Bin Zhang (co-mentor), and George Diaz(co-mentor)), meaningful collaborations, and personalized didactic mechanisms, which are outlined in this application. INSTITUTIONAL ENVIRONMENT. The Department of Genetics & Genomic Sciences at the Icahn School of Medicine at Mount Sinai is a hybrid world-class basic science and clinical program that offers a broad-based program of instruction, research, and clinical services. The faculty are experts in the application of molecular biology, data science, and somatic cell approaches for the study of genetic diseases. The environment provided in the department is ideal for the execution of the studies outlined in this application. RESEARCH PROJECT. There In understood. the hypothesis the in RNA transcriptome mechanisms, To with sclerosis/Frontotemporal FXTAS determine are currently no effective treatments for neurodegenerative disorders (NDDs). order to develop potential therapeutic targets the underlying biological mechanisms mus be more clearly Fragile X-associated tremor/ataxia syndrome (FXTAS) ffers an opportunity to gain insights into pathological mechanisms for an NDD disorder that stems from a defined genetic etiology. The overall is that protein clearance deficits are exacerbated by polypeptides and mRNA-FMR1 produced from CGG expansion. This results in neuronal response-driven increases in ubiquitin proteins that are deposited inclusions, leading to cell dysfuction, reactive inflammatory microglial and eventually neurodegeneration sequencing (bulk and single nuclei) will be used to qualitatively and quantitatively examine the in postmortem human tissue. Since NDDs involve complex and intertwined biological an unbiased and hypothesis-free approach for key molecular pathways discovery will be applied. identify the converging pathologica l processes in NDDS, the novel FXTAS datasets will be cross-examined available datasets of Alzheimer's Disease, Parkinson Disease and amyotrophic lateral ementia . This tudy has the potential to not only identify critical mechanisms driving pathogenesis that would acilitate the discovery of biomarkers and therapeutic targets but also pathways most central to disease through a cross-examination approach with other NDDs. , t o . d s f