This project aims to identify genetic causes of heritable movement disorders and define pathogenic mechanisms to improve diagnosis and enable targeted therapies. Parkinson’s disease, ataxias, spastic paraplegias, and dystonic or choreiform disorders are highly genetically heterogeneous, and many causative genes remain unknown. We will (1) recruit and characterize individuals and families with genetically unexplained movement disorders; (2) apply linkage/IBD analysis, next-generation sequencing, and CNV analysis to discover novel disease genes; and (3) investigate pathogenic mechanisms using patient tissues, induced pluripotent stem cell–derived neural and glial models, and Drosophila. Functional studies will focus on RAB39B, ATP6AP2, SAMD9L, and GBA, genes involved in endolysosomal trafficking and autophagy, pathways central to neurodegeneration. Integrated genomic, cellular, and model-organism approaches will define disease mechanisms, identify vulnerable cell types, and reveal therapeutic targets applicable across neurodegenerative disorders.
Funding Type: Federal
Regulatory variation that affects splicing of the Alzheimer’s disease risk gene TREM2
Alzheimer’s disease (AD) risk is strongly influenced by genetic variation, much of which lies in noncoding regions that regulate gene expression and RNA splicing. Protein-coding variants explain only ~30% of AD heritability, highlighting the need to functionally characterize regulatory variants. TREM2 is a microglia-specific immune receptor in which heterozygous missense variants increase late-onset AD risk, while biallelic loss-of-function variants cause early-onset dementia. TREM2 undergoes alternative splicing, but its transcript repertoire and regulation in human brain remain poorly defined. We identified a novel splice isoform lacking exon 2 (Δe2) that encodes a truncated protein with altered activity. Preliminary data show that AD- and dementia-associated variants shift splicing toward Δe2, reducing functional TREM2 dosage. We will define TREM2 isoforms in human brain, functionally assess regulatory variants affecting splicing, and analyze interactions between cis-variants and trans-acting splicing factors altered in AD, using long-read RNA sequencing and high-throughput functional assays.
Brain, Environment, and Alcohol Research (BEAR) Study
This project examines how brain responses to alcohol cues interact with everyday social contexts to shape drinking in young adult heavy drinkers. We pair multimodal neuroimaging (fMRI, EEG) with a 2-week ecological momentary assessment including transdermal alcohol monitoring and photo-based context capture. We test whether neural incentive salience predicts real-life intoxication, how social features (group size, familiarity, gender mix) influence drinking, and how perceived norms mediate these effects. We further assess whether incentive salience moderates context and norm influences. Findings will refine models of alcohol use disorder etiology and inform prevention and intervention strategies by linking precise brain markers with ecologically valid, context-rich assessments.
AMPERE (Augmented Momentary Personal Ecological Risk Evaluation)
Death by suicide is the 2nd leading cause of death among young adults in the United States. While most patients who die by suicide have had recent contact with their health care providers, the medical delivery system is poorly equipped to address this preventable issue. EMA (ecological momentary assessment) systems show promise as indicators of suicide risk and as a means of enhancing existing resources. However, little is known about how to apply these methods in the context of clinical care. The AMPERE study leverages existing work on EMAs and human-centered design principles to develop and pilot a prototype suicide risk monitoring system to support suicide risk management for adolescents and young adults (ages 16-30) within the UW Medicine Primary Care system.
Evaluating the role of virtual whole health in PC-MHI
The COVID-19 pandemic facilitated simultaneous paradigm shifts in healthcare delivery: virtual care (telehealth and videoconferencing) and the need for “Whole Person” healthcare that targets mind, body, and spirit, per recent US Surgeon General1 and National Academy of Medicine2 calls-to-action. The pandemic also highlighted treatment delivery inequities involving rural Veterans. The current proposal will address these trends, assessing virtual VA Whole Health care use in Primary Care-Mental Health Integration (PC-MHI) for rural and non-rural Veterans with chronic pain and co-occurring posttraumatic stress disorder (PTSD).
Evaluation of the VHA Acute Pain Service Expansion Program implementation and impact
The objective of the project is to evaluate the implementation and impact of the Acute Pain Services Expansion Program (APSEP), an expansion of the independent and formal set of services that provide comprehensive inpatient pain management consultative services and is designed to meet perioperative care needs of veterans receiving inpatient pain management.
Complementary and integrative health stepped care for co-occurring chronic pain and PTSD
The aim of the project is to conduct a pragmatic pilot trial of a CIH-based stepped care approach v. treatment as usual in two primary care settings (one rural and one urban). The pilot trial will focus on feasibility, acceptability, and appropriateness for providers and patients (e.g., randomization, retention, and treatment satisfaction) of the stepped care approach versus usual care (n=30 per site, N=60 total). Primary clinical outcomes are pain interference and PTSD symptoms at 6-months.
Behaviors and Executive Skills in T21 (BEST21)
We are conducting a study to understand the role of problem-solving in challenging behaviors for children with Down syndrome so that we can better understand the development of and treat these behaviors. If you agree to participate, this study will involve questionnaires, some of which may be completed at home. You would also attend an in-person visit that involves measuring your child’s naturally-occurring brain activity with EEG as well as cognitive assessments. We would schedule your visit around your schedule to the best of our ability and we can schedule this visit in a location that is convenient for you (UW, home visits, etc.). Participants will receive an $80 gift card to thank them for their time.
Beliefs and Attitudes for Successful Implementation in Schools – Teachers (BASIS-T)
We have developed – and are currently conducting a large-scale randomized trial of – at teacher-focused version of the Beliefs and Attitudes for Successful Implementation in Schools (BASIS) implementation strategy. BASIS-T is being tested in context of Positive Greetings at the Door (PGD) implementation. Details are available in a study protocol published in Implementation Science.
GATHER: Growing a Tribal Healing Effort through Research
The GATHER initiative aims to: 1) Coordinate a national research network to support tribally led research on etiology and prevention of overdose, substance use, mental health, and pain management. 2) Provide administrative support and shared resources to facilitate the successful completion of N CREW research projects. 3) Provide an administrative infrastructure, intellectual environment, and access to resources and initial support for investigators. 4) Provide research training and access to subject matter experts for investigators, staff, and students in the areas of cognitive, motivational, and behavior therapies, Indigenous approaches to research and healing, and multimodal holistic approaches to prevention and treatment. 5) Serve as a local, national, and international resource for dissemination of information and training to reduce risk in diverse tribal and urban Indian populations.
