Understanding the Genetic and Epigenetic Mechanisms in X-linked Dystonia Parkinsonism and Repeat Expansion Diseases - The purpose of this training is to elucidate the toxic mechanism(s) underlying the somatic expansion of the short tandem repeats (STRs) in repeat expansion diseases (REDs), using a suite of genomics, transcriptomics and cell-based strategies. Somatic expansion is thought to be the major driver of toxicity process(es) in vulnerable cell types once the STR exceeds length threshold(s), ultimately translating into disease onset. Understanding these mechanism(s) is crucial to identify the key pathogenic event(s) leading to disease and to develop effective and timely treatments for REDs. In the first section of this proposal, K99 phase, I will focus on the CCCTCT repeat, a noncoding STR modulating the disease process(s) in X-linked dystonia parkinsonism (XDP), a devastating neurological disorder. In aim 1, I will identify the CCCTCT length needed to trigger toxicity in vulnerable brain cells. In aim 2, I will investigate whether methylation is an event modulating the somatic expansion of the CCCTCT repeat. To successfully complete these aims, I will capitalize on my expertise acquired during my postdoctoral training in state-of-art technology, such as developing statistical models for high throughput genomic analyses while acquiring knowledge and skills in transposase-accessible chromatin with sequencing (ATAC-Seq), single-nuclear RNA-seq and nanopore sequencing analyses. In the second section of this proposal, the R00 phase, I will pair my training in statistical genomics, long-read sequencing and methylation approaches to translate the experience gained in XDP to the study of more complex REDs (e.g. the noncoding STR that is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)). During the independent phase, I will then focus on my long-term goal: identifying common and/or disease-specific modifiers of somatic expansion of REDs caused by noncoding STRs. A team of renowned experts in different aspects of REDs and somatic instability will provide mentorship to guide me through specialized training and ensure the establishment of an independent research career in the REDs field. The career development plan includes attending laboratory meetings and departmental discussions, national and international conferences, crafting research grant proposals, and preparing manuscripts. The training will take place at Massachusetts General Hospital (MGH), a prominent teaching hospital affiliated with Harvard Medical School (HMS) where both mentor (Dr. Wheeler) and co-mentor (Dr. Ozelius) have established long and prolific collaborations. MGH is renowned for its supportive research environment, advanced resources, and collaborative atmosphere conducive to learning and research in neurodegenerative diseases. Furthermore, MGH and HMS will facilitate my professional development by granting me access to various courses and workshops to enhance my presentation, leadership, and management skills. I am also an active member of Havard Brain Initiative (HBI), which promote cross-campus interaction to enhance research engaging the public in brain science, and together expanding its power for the betterment of human health and society.
