Johns Hopkins has a rich history of sleep-related research. Today we continue this tradition, studying everything from molecular control of sleep in fruit flies, to new treatments for sleep apnea.
Below is a sample of ongoing research studies.
For more information about participating in clinical research studies, please contact Tracy Klopfer at Tracy.Klopfer@jhmi.edu or call 410-550-4588. If you are interested in using our resources and expertise for sleep research, visit the Center for Interdisciplinary Sleep Research and Education (CISRE).
Actigraphic Assessment of Sleep Quality in the A4 Trial
The A4 Trial studies anti-amyloid therapy for prevention of cognitive decline in cognitively healthy participants with brain amyloid on PET scans. This study adds wrist actigraphy to assess links of sleep and rest/activity rhythms with amyloid burden, and the effect of anti-amyloid therapy on sleep and rhythms.
Team: Paul Rosenberg, Adam Spira, Mark Wu, Vadim Zipunnikov
Funding: 1R01AG049872-01 (MPIs: Rosenberg & Spira) 07/15/2015 – 03/31/2020
The ARIC Study of Midlife Sleep and Late-Life Brain Amyloid
Dementia and cognitive impairment are growing public health concerns. Knowledge of the importance of sleep-disordered breathing in the development of dementia, and particularly in the development of Alzheimer’s type of dementia (associated with β-amyloid deposition and neurodegeneration) is critical as it may lead to distinct avenues for development of therapies to prevent dementia or slow its progression. We propose to study the extent to which sleep-disordered breathing is associated with neuroimaging evidence of amyloid deposition, brain atrophy, and cognitive decline almost 20 years later.
Team: Adam Spira, Rebecca Gottesman, Mark Wu, Naresh Punjabi, Vadim Zipunnikov
Funding: 1RF1AG050745 (MPIs: Spira & Gottesman) 06/01/2016 – 05/31/2021
Deriving and validating sleep phenotypes from wrist activity monitors
This project evaluates data from consumer wrist activity monitors in order to characterize sleep and circadian tendencies in the general population. Based on Under Armour wrist actigraphy monitoring, the project has developed novel tools and algorithms for classifying common sleep disorders in the general population. It is designed to provide tools and insights that help end-users improve their sleep and related outcomes including athletic performance, injury rates, cold susceptibility and general well-being. The project is currently being extended to a group of collegiate athletes in whom time constraints from practice schedules and academic and social demands can impact on sleep health.
Team: Alan Schwartz, Luu Pham, Frank Sgambati
Funding: Under Armour
Links: Hopkins and Under Armour Bring Science to Connected Fitness
Evaluation of WatchPAT Device for Home Sleep Testing
Several home sleep apnea testing devices are available for screening patients for the presence and for determining the severity of sleep apnea. We have developed and validated a unique technology for characterizing sleep apnea based on alterations in actigraphy, oxyhemoglobin saturation, snoring and peripheral arterial tonometry in the finger. The project evaluates the performance and accuracy of Itamar’s Watch-PAT device in specific patient populations susceptible to the development of sleep disordered breathing. The project is designed to train end-users in the assessment of Watch PAT recordings, and provide them the ability edit and verify results from this device.
Team: Alan Schwartz, Hartmut Schneider, Larissa Sanglard Sperandio, Mudi Sowho, Zhi-gang Zhang, Frank Sgambati, Tracy Klopfer, Erin Hawks
Funding: Itamar Medical
Genetic and Epigenetic Links of Sleep to Alzheimer’s and Other Aging-Related Diseases
This research will identify epigenetic modifications and changes in gene/protein expression associated with poor sleep and sleep-disordered breathing; the subset of those changes linked to AD biomarkers, measures of brain aging, and cognitive impairment; and links of poor sleep and SDB with accelerated cellular aging.
Team: Adam Spira, Mark Wu, Brion Maher, Susan Resnick, Luigi Ferrucci
Funding: Johns Hopkins University Catalyst Award
Hemodynamic Responses to Upper Airway Obstruction in Marfan Syndrome
Upper airway obstruction (UAO) during sleep may be a source of cardiovascular stress in persons with Marfan syndrome. We are examining the effects of nocturnal UAO on hemodynamic function as well as on aortic and cardiac wall stress in persons with Marfan syndrome having haploinsufficient and dominant negative genotypes. This project will be the first to uncover UAO as a new mechanism for increased cardiovascular morbidity in Marfan syndrome and will also demonstrate the effect of CPAP treatment as a potential intervention for adverse cardiovascular events in Marfan syndrome.
Team: Mudiaga Sowho, Enid Neptune, Jonathan Jun, Susheel Patil, Gretchen MacCarrick, Hartmut Schneider.
Funding: NIH- 5 T32 HL 110952-5 (07/17- 06/20)
High altitude sleep research
Many populations reside at high altitude and are exposed to chronic low oxygen levels. During sleep, oxygenation plummets even further and triggers breathing pauses. We are studying the impact of altitude and low oxygen levels during sleep as part of the CRONICAS Cohort study, which has a high altitude site at Puno, Peru (3825 m, or 2.5 miles above sea level). We found that the prevalence of sleep apnea increased in proportion to reductions in oxygen levels during wakefulness and that patterns of oxygenation during sleep predicted worsening glucose control and chronic mountain sickness. Our current work focuses on developing inexpensive and readily deployable treatments for sleep apnea and low oxygen levels in highlanders.
Team: Luu Pham, Alan Schwartz, William Checkley, Dina Goodman
Funding: NIH (Schwartz & Checkely) 1R34HL135360-01
Lymphocyte CpG methylation changes and brain pathology in Restless Legs Syndrome (RLS)
Early exposure to iron deficiency during pregnancy and in infancy and childhood appears to increase risk of developing restless leg syndrome (RLS), a common debilitating disease, later in life. Epigenetic changes may provide an important link between prior iron deficiency and later disease development. Epigenetic changes in CpG methylation in lymphocytes is the primary source of DNA. As iron deficiency anemia is associated with 6-fold increase in RLS expression, we utilize a population of women with iron deficiency anemia in which we delineate two groups: disease-susceptible and disease-resistant groups.
Team: Christopher Earley, Richard Allen, Satish Shanbhag, Rahki Naik, Peter van Zijl, Xi Li, Zachary Kaminsky. Coordinators : Alaina Hergenroeder and Emily Rost
Funding: NIH R01 NS101283 (Earley) 6/1/17-5/31/22
Maternal Sleep and Sleep Disturbance in Relation to the Developing Fetus
Sleep disturbances and sleep apnea have been implicated in pregnancy complications including gestational diabetes and preeclampsia. However, limited attention has been directed at understanding how maternal sleep disruption directly affects the fetus. We are examining immediate and persistent effects of maternal sleep disruption and maternal sleep-disordered breathing during pregnancy on the developing fetus.
Team: Janet DiPietro, Grace Pien, Janice Henderson, Frank Sgambati, Heather Watson
Funding: NIH R01HD079411 (DiPietro) 7/7/14-6/30/19
Metabolic Consequences of Sleep Apnea
Sleep apnea patients are at increased risk for diabetes and cardiovascular disease, but mechanisms are unclear. Our laboratory is studying effects of sleep apnea on nocturnal metabolism sleeping with or without wearing their CPAP. Using this approach, we discovered that OSA increases plasma free fatty acids (FFA) and glucose during sleep. Now, we are examining the underlying mechanisms and consequences of OSA-induced FFA elevation using techniques such as beta blockade and stable isotopes.
Team: Jonathan Jun, Chenjuan Gu, Naresh Punjabi, Robert Wolfe (UAMS), Elisabet Borsheim (UAMS), Alice Ryan (Univ of Maryland)
Funding: R01HL135483 (Jun) 2/1/2018 – 1/1/2023; R03HL138068 (Jun) 9/1/17 – 7/31/19
Metabolic effects of eating late dinner
The timing of meals may be important for weight control and heart health. Eating meals later in the day is linked with obesity and cardiovascular disease. We hypothesize that eating close to bedtime may delay the oxidation of fat impair nocturnal metabolism. To test this hypothesis we are performing a randomized trial of eating dinner at the “usual” time (around 6:00 PM) versus at a later time (around 10:00 PM).
Team: Jonathan Jun, Chenjuan Gu, Daisy Duan, Luu Pham, Vsevolod Polotsky
Metabolic effects of hypoxia
Sleep apnea causes periods of low oxygenation. Although sleep apnea is strongly linked to metabolic diseases, the mechanisms for development of these metabolic diseases is unknown. Low oxygen levels during wakefulness increases blood glucose and markers of inflammation. The effects of low oxygen during sleep on metabolism have not been well studied. We are recruiting healthy volunteers in a study to examine the effects of breathing low oxygen on metabolism and gene expression in inflammatory pathways during sleep.
Team: Luu Pham and Alan Schwartz
Funding: The American Heart Association (Pham) 07/01/17-06/30/19, 17MCPRP3367111
OSA and Glycemic Variability in Type 2 Diabetes Mellitus
Emerging data suggests that obstructive sleep apnea (OSA) can alter glucose metabolism and increase cardio-metabolic risk. While continuous positive airway pressure therapy (CPAP) is effective in treating OSA, its effects on glycemic variability and postprandial hyperglycemia are unknown. The central focus of this proposal is to delineate the impact of OSA and its treatment with CPAP on glycemic measures, such as postprandial hyperglycemia and glycemic variability that are known to predict future cardiovascular risk.
Team: Nisha Aurora, Naresh Punjabi
Funding: K23HL118414-04 (PI: Aurora) 09/09/2014 – 06/30/2019
Prospective study of dayZz survey tool for diagnosing common sleep disorders.
Sleep disorders are commonly encountered throughout society at large, and a paucity of resources are available to diagnose and manage these problems as the arise in real-time. This study compares the performance of a standardized survey instrument with clinician-generated diagnoses of common sleep disorders in a community based sample. It seeks to enhance the recognition and expedite the management of common sleep disorders by providing easy access to diagnostic tools and insights as well as management strategies to patients themselves.
Team: Alan Schwartz, Larissa Sanglard Sperandio, Tracy Klopfer, Frank Sgambati, Erin Hawks
Poor Sleep, Altered Circadian Rhythms, and Alzheimer’s Disease
Poor sleep may contribute to cognitive decline and progression of Alzheimer’s Disease. To study this phenomenon we will collect wrist actigraphy data for seven 24-hour periods in the Baltimore Longitudinal Study of Aging, which contains repeated measures of cognition with adjudication of cognitive status, [11C]-Pittsburgh compound B (PiB) positron emission tomography (PET)-measured β-amyloid, and structural magnetic resonance imaging (MRI)-measured atrophy. Participants who are cognitively normal at baseline and complete PiB PET will also complete polysomnography, permitting us to determine the extent to which poor sleep and altered rest/activity rhythms are prospectively associated with neuroimaging biomarkers of β-amyloid deposition and neurodegeneration, and with cognitive decline.
Team: Adam Spira, Mark Wu, Naresh Punjabi, Vadim Zipunnikov, Ciprian Crainiceanu, Susan Resnick, Eleanor Simonsick, Luigi Ferrucci
Funding: 1R01AG050507-01 (Spira) 09/01/2015 – 05/31/2020
Randomized, placebo-controlled trial of ferric carboxymaltose in Restless Legs Syndrome patients with iron-deficiency anemia.
RLS is increased in prevalence and severity in patients that have iron deficiency anemia. This study examines (1) whether intravenous iron therapy can more effectively improve symptoms and (2) whether treating the symptoms is more important than simply treating the anemia. This is a three-phase clinical trial. Phase I: randomized, double-blind, placebo-controlled 6-week assessment of treatment with 1500 mg ferric carboxymaltose. Phase II: open label, treatment with 1500 mg ferric carboxymaltose in non-responders in Phase I. Phase III: 46-week follow up with intermittent treatment with 750 mg ferric carboxymaltose if patients have a return of RLS symptoms and their ferritin < 300 ug/l.
Team: Christopher Earley (PI), Richard Allen, Satish Shanbhag, Rahki Naik, Peter van Zijl, Xi Li. Coordinators: Emily Rost and Alaina Hergenroeder.
Funding: Luitpold Pharmaceutical, Inc. Protocol VIT 15042. IND #73076
Sleep patterns, delirium and mobility in hospitalized children
Sleep fragmentation is common in children admitted to the hospital during a time of neurocognitive development. Sleep disturbances that begin in the Pediatric ICU may have lasting impacts including psychological and psychiatric morbidities. Abnormal sleep-wake patterns may increase the risk of delirium and also decreases patient participation in early mobilization activities. We are investigating the impact of sleep fragmentation on delirium incidence and early mobilization. In addition, we are collaborating with Under Armour to develop an intervention utilizing fitness trackers for adolescents in the hospital.
Team: Sapna Kudchadkar, Tracie Walker, Aaron Hsu, Sean Barnes
Partners/funding: 1R21HD093369-01, Under Armour
Sleep-related Clinical Trials Data Scoring and Coordinating Center
The project aims to score and analyze in-lab sleep studies, which are performed at clinical trial sites. To date, this core facility has develop a versatile laboratory and IT backbone to coordinate the acquisition, reduction, archiving and analysis of sleep recordings and survey data in sleep cohorts and clinical trials. It has provided support for interdisciplinary sleep researchers at Johns Hopkins and elsewhere. The Center for Interdisciplinary Sleep Research and Education (CISRE) has supported multi-center clinical trials and cohort studies at Johns Hopkins and at centers throughout the world.
Team: Alan Schwartz, Hartmut Schneider, Frank Sgambati, Erin Hawks
Funding: Johns Hopkins Center for Interdisciplinary Sleep Research and Education (CISRE)
Treating Sleep apnea in type 2 diabetes mellitus
Emerging data suggests that obstructive sleep apnea can alter glucose metabolism and worsen glycemic control in patients with type 2 diabetes mellitus. While continuous positive airway pressure therapy (CPAP) is effective in treating obstructive sleep apnea, its effects on glycemic control, postprandial hyperglycemia, blood pressure, and endothelial function are unknown. We propose to conduct a single center, randomized controlled trial of CPAP vs. lifestyle counseling for 6 months in patients with type 2 diabetes to determine whether CPAP treatment for obstructive sleep apnea can improve glycemic, hemodynamic, and vascular outcomes. We propose to conduct a randomized control trial in subjects with diabetes and moderate to severe OSA who will be randomly assigned for 6 months to CPAP with lifestyle counseling or lifestyle counseling alone.
Team: Naresh Punjabi, Nisha Aurora,
Funding: R01HL117167-04 (PI: Punjabi) 06/01/2014 – 05/31/2018
Asthma, high fat diet, and particulate matter
Obesity or a high-fat diet can aggravate airway hyper-reactivity and asthma. Furthermore, air pollution with particulate matter can induce or exacerbate asthma. Our laboratory is investigating the interaction of particulate matter with diet on airway physiology and inflammation in mice. We hope that this project will lead to an understanding of the relationship between asthma, nutrition, and air quality and provide possible targets for intervention.
Team: Seva Polotsky
Funding: P50 ES018176 (Hansel) 9/1/15-08/31/19
Chemogenetic stimulation of hypoglossal neurons to probe targets for sleep apnea therapy
The pathogenesis of sleep apnea has been linked to a defect in neuromuscular control of the pharynx. Our laboratory has pioneered a technique to augment upper airway patency by deploying designer receptors exclusively activated by designer drug (DREADD) in the hypoglossal motor neuron of mice. Activation of the DREADDs dilated the pharynx. We are now refining our technique by improving the specificity of DREADD delivery, using Cre-Lox technology and retrograde viral transfection techniques.
Team: Thomaz Fleury, Huy Pho, Alan Schwartz, Seva Polotsky
Funding: R01HL138932 (Polotsky) 8/4/17 – 6/30/21; 16POST31000017 (Fluery) 7/1/16 -6/30/18
Hypoglossal stimulation as a treatment for sleep apnea
Airway narrowing and closure leading to sleep apnea occurs because of an excessive decrease in genioglossus muscle tone. Thus, OSA may be treated by delivering electrical stimulation of the hypoglossal nerve, which controls the tone of the tongue muscle during sleep. Already, one such device has been tested in clinical trials and is approved for OSA treatment in highly selected patients who cannot tolerate CPAP. However, existing technology only stimulates the genioglossus muscle in a non-targeted manner which may limit its effectiveness. Our laboratory is examining the effects of selective stimulation of various lingual muscles, singly or in combination, on upper airway function.
Team: Alan Schwartz, Thomaz Fleury
Funding: lmThera, Inc.
Leptin and control of breathing
Leptin is a hormone produced by adipose tissue that regulates appetite and metabolism. Leptin deficient mice develop obesity. It was later discovered that these mice also chronically hypoventilate, and replacing leptin improved ventilation and sensitivity to carbon dioxide. Our lab also showed that replacing leptin improves upper airway function and sleep disordered breathing in mice. Now, our lab is exploring signaling pathways of leptin in the brain to localize possible therapeutic targets.
Team: Huy Pho, Seva Polotsky, Alan Schwartz
Funding: R01 HL128970 (Polotsky) 8/10/15 – 5/31/19
Leptin signaling in the carotid body
Leptin reduces food intake and increases metabolic rate. However, leptin may be a “double-edged sword” since it can also increase blood pressure. Our lab discovered that leptin binds to receptors on the carotid body and can increase blood pressure by activating channels in these cells. Now, we are using viral transfection to manipulate leptin receptor expression in the carotid body, responses to leptin infusion.
Team: Mi-Kyung Shin, Candela Cabellero, Luis Prichard, Seva Polotsky, James Sham, Alan Schwartz
Funding: R01HL133100 (Polotsky) 7/1/16 – 2/29/20
Molecular and Circuit Mechanisms Encoding Homeostatic Sleep Drive
Prolonged wakefulness (such as under conditions of sleep deprivation) is known to lead to increased rebound sleep. Our lab identified a novel neural circuit that encodes sleep drive in the fruit fly Drosophila melanogaster. We hypothesize that many signaling mechanisms resulting from behavioral states or environmental changes may act upon this circuit to suppress or increase sleep drive. Our team is currently working on identifying and characterizing the upstream signaling inputs and downstream targets of this homeostatic sleep circuit, as well as the molecular underpinnings of decision-making by this neural circuit. Findings arising from this research will shed light on the mechanisms of homeostatic regulation of sleep.
Team: Margaret Ho, Masashi Tabuchi, Ian Blum, Mark Wu
Funding: NIH R01NS100792-01A1 (Wu)