This is an application for a K01 award for Dr. Jennifer Yokoyama, a neurogenetics fellow at the University of California, San Francisco Memory and Aging Center (MAC). Dr. Yokoyama is establishing herself as a young geneticist conducting clinical research on neurodegenerative disease. This K01 will provide Dr. Yokoyama with the support necessary to accomplish the following goals: (1) to gain experience in the use of next-generation sequencing for transcriptomics; (2) to become proficient in clinical research methodologies, including interpretation of genetic data in clinical settings; (3) to obtain an understanding of advanced statistics; and (4) to develop an independent research career. To achieve these goals, Dr. Yokoyama has assembled a mentoring team including two primary mentors: Drs. Bruce Miller (a behavioral neurologist with expertise in neurodegenerative disease) and Matthew State (a human geneticist and child psychiatrist with expertise in gene discovery); three co-mentors: Drs. Howard Rosen (a neurologist with expertise in clinical research in neurodegenerative disease), Kristine Yaffe (a neurologist and psychiatrist with expertise in epidemiology/biostatistics), and William Seeley (a neurologist with expertise in neuropathology); and one collaborator: Dr. Giovanni Coppola (a neurologist with expertise in human genetics and bioinformatics). The proposed research project focuses on neurodegenerative diseases caused by repeat expansion of C9ORF72 (C9+), which was recently identified as the most common cause of both familial frontotemporal dementia (FTD) and familial amyotrophic lateral sclerosis (ALS). Dr. Yokoyama will begin to elucidate the biological mechanism by which C9+ can cause phenotypic variability (FTD versus ALS) by studying the relationship of peripheral gene expression to affected brain tissue in C9+ FTD and C9+ ALS.
Aim 1 : Dr. Yokoyama will determine whether peripheral RNA expression differentiates C9+ FTD from C9+ ALS using deep RNA sequencing.
Aim 2 : Dr. Yokoyama will test whether RNA expression in brain regions most vulnerable to C9+ pathology varies based on C9ORF72 expansion length in C9+ FTD and C9+ ALS patients.
Aim 3 : Dr. Yokoyama will perform exploratory genome-wide association studies to identify genetic variation that drives brain region-specific C9ORF72 expansion and clinical syndrome. The ultimate goal of this project is to identify biomarkers that can be used to screen for modifiers of disease and track clinical progression. The proposed research is innovative because it seeks to explore the relationship between changes in gene expression and local brain pathology, and to link these to novel genetic variation that may ultimately drive clinical disease presentation. Results from the proposed research will make significant contributions to our understanding of biological mechanisms underlying C9ORF72 expansion-mediated disease and identify informative biomarkers that could lead to novel therapies. Dr. Yokoyama's K01 training will prepare her to conduct cutting edge genetic studies of brain disorders using sophisticated neuroanatomical phenotypes.

Public Health Relevance

The proposed research is relevant to public health because it begins to address the fundamental question of how shared genetic risk can result in phenotypic variability in neuropsychiatric conditions. This work would result in elucidation of peripheral biomarkers with known relationships to pathological changes in the brain associated with frontotemporal dementia and amyotrophic lateral sclerosis that could be used for future studies to identify disease modifiers and to monitor clinical progression in intervention trials. This projct is highly relevant to the NIA's mission because it supports the conduct of genetic, biological, and clinical aging research and fosters the development of a clinical research scientist in aging.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Scientist Development Award - Research & Training (K01)
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Study Section
Neuroscience of Aging Review Committee (NIA)
Program Officer
Petanceska, Suzana
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Bonham, Luke W; Sirkis, Daniel W; Fan, Jia et al. (2017) Identification of a rare coding variant in TREM2 in a Chinese individual with Alzheimer's disease. Neurocase 23:65-69
Ferrari, Raffaele; Wang, Yunpeng; Vandrovcova, Jana et al. (2017) Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer's and Parkinson's diseases. J Neurol Neurosurg Psychiatry 88:152-164
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Yokoyama, Jennifer S; Marx, Gabe; Brown, Jesse A et al. (2017) Systemic klotho is associated with KLOTHO variation and predicts intrinsic cortical connectivity in healthy human aging. Brain Imaging Behav 11:391-400
Chen, Jason; Yu, Jin-Tai; Wojta, Kevin et al. (2017) Genome-wide association study identifies MAPT locus influencing human plasma tau levels. Neurology 88:669-676
Bonham, Luke W; Geier, Ethan G; Fan, Chun C et al. (2016) Age-dependent effects of APOE ?4 in preclinical Alzheimer's disease. Ann Clin Transl Neurol 3:668-77
Sirkis, Daniel W; Bonham, Luke W; Aparicio, Renan E et al. (2016) Rare TREM2 variants associated with Alzheimer's disease display reduced cell surface expression. Acta Neuropathol Commun 4:98

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