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.
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.
|Bonham, Luke W; Evans, Daniel S; Liu, Yongmei et al. (2018) Neurotransmitter Pathway Genes in Cognitive Decline During Aging: Evidence for GNG4 and KCNQ2 Genes. Am J Alzheimers Dis Other Demen 33:153-165|
|Chen, Jason A; Chen, Zhongbo; Won, Hyejung et al. (2018) Joint genome-wide association study of progressive supranuclear palsy identifies novel susceptibility loci and genetic correlation to neurodegenerative diseases. Mol Neurodegener 13:41|
|Bonham, Luke W; Steele, Natasha Z R; Karch, Celeste M et al. (2018) Protein network analysis reveals selectively vulnerable regions and biological processes in FTD. Neurol Genet 4:e266|
|Broce, Iris; Karch, Celeste M; Wen, Natalie et al. (2018) Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies. PLoS Med 15:e1002487|
|Bonham, Luke W; Karch, Celeste M; Fan, Chun C et al. (2018) CXCR4 involvement in neurodegenerative diseases. Transl Psychiatry 8:73|
|Broce, Iris J; Tan, Chin Hong; Fan, Chun Chieh et al. (2018) Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer's disease. Acta Neuropathol :|
|Carr, Jessie S; Bonham, Luke W; Morgans, Alicia K et al. (2018) Genetic Variation in the Androgen Receptor and Measures of Plasma Testosterone Levels Suggest Androgen Dysfunction in Alzheimer's Disease. Front Neurosci 12:529|
|Vatsavayai, Sarat C; Nana, Alissa L; Yokoyama, Jennifer S et al. (2018) C9orf72-FTD/ALS pathogenesis: evidence from human neuropathological studies. Acta Neuropathol :|
|Tan, Chin Hong; Fan, Chun Chieh; Mormino, Elizabeth C et al. (2018) Polygenic hazard score: an enrichment marker for Alzheimer's associated amyloid and tau deposition. Acta Neuropathol 135:85-93|
|Geier, Ethan G; Bourdenx, Mathieu; Storm, Nadia J et al. (2018) Rare variants in the neuronal ceroid lipofuscinosis gene MFSD8 are candidate risk factors for frontotemporal dementia. Acta Neuropathol :|
Showing the most recent 10 out of 34 publications