Narcolepsy is a debilitating and incurable sleep disorder that affects 1 in 2000 individuals. Narcolepsy is caused by the loss of a unique population of hypothalamic neurons that produce the neuropeptide hypocretin (HCRT, also known as orexin). The cause of human HCRT neuron loss is unknown, largely because it has been impossible to directly study human HCRT neurons. To address this limitation, I developed methods to derive induced pluripotent stem (iPS) cells from narcoleptic patients and to differentiate these cells into HCRT neurons in vitro. Now, a combination of hypothesis-driven and discovery-driven approaches will be used to search for disease-relevant differences between control and patient-derived HCRT neurons. In particular, these two cell populations will be compared in the presence or absence of environmental stressors to search for differences in their survival, morphology, electrophysiology, or transcriptional profiles. Furthermore, the effect of mutations in the DNA methyltransferase DNMT1 on HCRT neuron survival will be tested since DNMT1 mutations are sufficient to cause familial narcolepsy, and polymorphisms in the DNMT1 locus are associated with sporadic narcolepsy. Finally, human HCRT neurons will be transplanted into narcoleptic mice to test whether grafted neurons are able to rescue narcoleptic symptoms. Together, these studies have the potential to identify environmental and genetic factors leading to HCRT neuron loss in narcolepsy and will test a potentially curative treatment for this common but neglected disease.

Public Health Relevance

Narcolepsy is an incurable and debilitating sleep disorder that affects 1 in 2000 individuals and is caused by the loss of hypocretin (HCRT) neurons. The proposed study will compare in vitro-derived HCRT neurons from control and narcoleptic patients and search for differences that contribute to HCRT neuron loss in narcolepsy. Human HCRT neurons will then be transplanted into narcoleptic mice to explore a potentially curative cell replacement therapy for narcolepsy.

Agency
National Institute of Health (NIH)
Type
Career Transition Award (K99)
Project #
5K99NS083713-02
Application #
8685362
Study Section
Neurological Sciences Training Initial Review Group (NST)
Program Officer
He, Janet
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Harvard University
Department
Anatomy/Cell Biology
Type
Schools of Arts and Sciences
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02138