Unveiling the histological and molecular basis of sleep disturbances in neurodegenerative diseases
Lea Grinberg, Professor
UC San Francisco
Applications for Fall 2024 are closed for this project.
Background: Sleep disturbance is common among patients with neurodegenerative diseases. For instance, patients with Alzheimer’s disease (AD) experience excessive daytime sleepiness and sundowning. Progressive supranuclear palsy (PSP) features hyperarousal and decreased homeostatic sleep drive. Sleep disturbance generally precedes disease-defining symptoms, often by decades, suggesting that dysregulation of sleep is important in the early pathogenesis of neurodegeneration. We are characterizing the deposition of tau pathology in areas involved in sleep regulation in patients with tauopathies.
Tauopathies are a group of neurodegenerative diseases that feature the deposition of abnormal phospho-tau protein in the brain. The most common tauopathies are AD, PSP, corticobasal degeneration, and Pick’s disease. Tauopathies are progressive and there is no treatment available to date. Among the plethora of disruptive clinical symptoms, most patients suffer from sleep dysfunction which directly impacts the patient and caregiver’s quality of life. Understanding the biological basis of the sleep disturbances in each tauopathy may help to provide personalized symptomatic treatment and improve the patient quality of life.
Our lab confirmed profound degeneration of wake-promoting neurons in AD using stereology in postmortem brains from patients with tauopathies. In addition, we revealed subcortical neuronal correlates of sleepness in neurodegenerative diseases.
Goal: Given that tau inclusions are associated with the selective vulnerabilities of sleep- and wake-regulating neurons, the overall goal of this project is to quantify tau-driven up- and down-regulated genomic and proteomic expression in sleep- and wake-regulating nuclei of postmortem tissues. This goal has widespread potential for a clearer explanation of the fundamental mechanism of sleep disorders between neurodegenerative diseases.
Specific aim: We will conduct a wet-lab basis histologic study, using 1) RNAscope to trace region-of-interest (ROI) for digital spatial profiling (DSP), 2) DSP to quantify differentially expressed pathology associated-proteins/genes in the target ROI, 3) nCounter to quantify differentially expressed circadian genes, 4) histologic validation using cell counting with stereology
Role: Background: Sleep disturbance is common among patients with neurodegenerative diseases. For instance, patients with Alzheimer’s disease (AD) experience excessive daytime sleepiness and sundowning. Progressive supranuclear palsy (PSP) features hyperarousal and decreased homeostatic sleep drive. Sleep disturbance generally precedes disease-defining symptoms, often by decades, suggesting that dysregulation of sleep is important in the early pathogenesis of neurodegeneration. We are characterizing the deposition of tau pathology in areas involved in sleep regulation in patients with tauopathies.
Tauopathies are a group of neurodegenerative diseases that feature the deposition of abnormal phospho-tau protein in the brain. The most common tauopathies are AD, PSP, corticobasal degeneration, and Pick’s disease. Tauopathies are progressive and there is no treatment available to date. Among the plethora of disruptive clinical symptoms, most patients suffer from sleep dysfunction which directly impacts the patient and caregiver’s quality of life. Understanding the biological basis of the sleep disturbances in each tauopathy may help to provide personalized symptomatic treatment and improve the patient quality of life.
Our lab confirmed profound degeneration of wake-promoting neurons in AD using stereology in postmortem brains from patients with tauopathies. In addition, we revealed subcortical neuronal correlates of sleepness in neurodegenerative diseases.
The student will conduct a wet-lab basis histologic study, using 1) RNAscope to trace region-of-interest (ROI) for digital spatial profiling (DSP), 2) DSP to quantify differentially expressed pathology associated-proteins/genes in the target ROI, 3) nCounter to quantify differentially expressed circadian genes, 4) histologic validation using cell counting with stereology
Qualifications: 10+hours/week -in person availability (at least 5+hours/consecutive day) -comfortable with the basic wet-lab skills (stable hand, patience, and punctual) and microscopy (bright-field and fluorescent) - good team player - quick learner - dependable - knowledge of neuroanatomy, photoshop, and R, and passion for neurodegenerative disease research are pluses .
Day-to-day supervisor for this project: Gowoon Son and Abhijit Saptati
Hours: 9-11 hrs
Off-Campus Research Site: UCSF - MISSION BAY 675 Nelson rising Lane, room 292 San Francisco, CA 94158
Biological & Health Sciences