Narcolepsy with Cataplexy (N/C) is a common sleep disorder, but very little is understood about the underlyingmechanism that causes N/C and why symptoms are severe in some patients but not in others. N/C is causedby selective loss of the hypothalamic neurons that produce the orexin neuropeptides and is strongly associatedwith the Major Histocompatibility Complex (MHC) class II allele DQB1 *0602. We hypothesize that N/C iscaused by CD4+ or CD8+ T cells response directed against the hypothalamic neurons producing the orexinneuropeptides, and that a more aggressive immune response results in increased severity of N/C. Thishypothesis is supported by a number of publications suggesting a causal role of the cellular immune responsein N/C as well as our own preliminary data. Our long term goal is to understand the cause of N/C and thedeterminants of disease severity. In doing so, we will also devise a much needed blood test for the earlydiagnosis of NC and prediction of disease severity. Our objectives are to determine whether N/C patientsmount a cellular immune response to orexin peptides and whether this response is associated with moresevere symptoms. The rationale is that these proposed studies will enable us to develop a blood test for earlydiagnosis of N/C and predictor of disease severity.To test these hypotheses, we will pursue the following set of Specific Aims:
Aim 1) Correlate disease severity with the cellular immune response to orexin neuropeptides in DQB1*0602+ Narcolepsy with Cataplexy patients. We will measure narcolepsy symptoms severity using well-validated scales and correlate symptom severity with the reactivity of CD4+ or CD8+ T cells to orexin peptidesusing three different assays: 1) Intracellular Cytokine Staining (ICS) assay 2) Luminex xMAP bead array on cellculture supernatant and 3) RT-qPCR for cytokine mRNA on cellular RNA .
Aim 2) Identify immunodominant orexin epitopes recognized by CD4+ or CD8+ T cells in DQB1 *0602+Narcolepsy with Cataplexy patients. We will map orexin epitopes in N/C patients using ICS and devise adiagnostic blood test and predictor of disease severity for N/C.The approach is innovative, because it departs significantly from the status quo by focusing on the cellularmechanisms leading to N/C. The proposed research is significant because it will allow us to identify theimmunopathogenic mechanisms leading to N/C, develop a blood test for early diagnosis of N/C and predictdisease severity. The knowledge gained from these studies will also have far reaching implications inadvancing the fields of Sleep Disorders and Neuro-Immunology.

Public Health Relevance

The proposed research is relevant to public health because it will have an important positive impact on theclinical management of Narcolepsy with Cataplexy patients; and provide a novel diagnostic test and targets fortherapeutic interventions. Thus; the proposed research is relevant to the part of NINDS' mission that pertainsto developing fundamental knowledge to alleviate the burdens of neurological diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
7R21NS099787-02
Application #
9404243
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
He, Janet
Project Start
2016-09-01
Project End
2018-08-31
Budget Start
2016-09-05
Budget End
2017-08-31
Support Year
2
Fiscal Year
2016
Total Cost
$271,267
Indirect Cost
$89,372
Name
Rush University Medical Center
Department
Neurosciences
Type
Schools of Medicine
DUNS #
068610245
City
Chicago
State
IL
Country
United States
Zip Code
60612