Thomas Kilduff

Last updated
Thomas Kilduff
Alma mater University of Florida
Stanford University
Known forDiscovery of hypocretin
Awards2009 AAAS Fellow
Scientific career
FieldsNeuroscience, particularly the neurobiology of sleep and wakefulness
Institutions Ames Research Center
Stanford University School of Medicine
SRI International
Academic advisors Wilse B. Webb, Craig Heller, Bill A. Williams, William C. Dement

Thomas S. Kilduff is an American neuroscientist and the director of SRI International's Center for Neuroscience. He specializes in neurobiology related to sleep and wakefulness, and was involved in the discovery of hypocretin (also known as orexin), [1] [2] a neuropeptide system that is highly involved in wakefulness regulation. [3] [4] [5]

Contents

His group at SRI International also discovered an unusual neuronal population in the cerebral cortex that is activated during sleep. [6] [7] [8]

He is also a consulting professor at the Stanford University School of Medicine's Department of Psychiatry and Behavioral Sciences. [3]

Education

Kilduff obtained a B.S. from the University of Florida and earned an M.S. and a Ph.D. in biological sciences from Stanford University, where he was also awarded fellowships from the Danforth Foundation, the Grass Foundation, and the National Science Foundation. [9]

Career

Kilduff was a senior research scientist at Stanford University's Center for Sleep and Circadian Neurobiology. [9] He was also a visiting scientist in the Scripps Research Institute's Department of Molecular Biology, a visiting professor at the University of Perugia's Istituto di Biologia Cellulare, and a National Academy of Sciences National Research Council research associate at NASA's Ames Research Center. [10]

In 1999, Kilduff joined SRI International as part of a new molecular neurobiology group, where he subsequently founded the Sleep Neurobiology Program before becoming director of the Center for Neuroscience. [10] [11]

Research

Kilduff's early research focused on the neural control of mammalian hibernation [12] [13] [14] and circadian rhythms. [15] [16] [17]

Kilduff and scientists at the Scripps Research Institute co-discovered hypocretin (also known as orexin), a neuropeptide system that is involved in the control of wakefulness. [11] Subsequent research established that the hypocretin neurons degenerate in the sleep disorder narcolepsy and is the likely cause of this disorder. [18] [19]

Awards and memberships

He was named a Fellow Member of the American Association for the Advancement of Science in the December 18, 2009 issue of Science . [9] [20] He was named an SRI Fellow in 2010 [3] and a Distinguished Scientist by the SRS in 2017. [21]

He is a member of the Society for Neuroscience has served on the boards of the Associated Professional Sleep Societies, the Sleep Research Society, and was a Founding Member of the Sleep Research Society Foundation. [11] [22]

See also

Related Research Articles

<span class="mw-page-title-main">Orexin</span> Neuropeptide that regulates arousal, wakefulness, and appetite.

Orexin, also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. It exists in the forms of orexin-A and orexin-B. The most common form of narcolepsy, type 1, in which the individual experiences brief losses of muscle tone, is caused by a lack of orexin in the brain due to destruction of the cells that produce it.

<span class="mw-page-title-main">Cholecystokinin</span> Hormone of the gastrointestinal system

Cholecystokinin is a peptide hormone of the gastrointestinal system responsible for stimulating the digestion of fat and protein. Cholecystokinin, formerly called pancreozymin, is synthesized and secreted by enteroendocrine cells in the duodenum, the first segment of the small intestine. Its presence causes the release of digestive enzymes and bile from the pancreas and gallbladder, respectively, and also acts as a hunger suppressant.

Wakefulness is a daily recurring brain state and state of consciousness in which an individual is conscious and engages in coherent cognitive and behavioral responses to the external world.

<span class="mw-page-title-main">Reticular formation</span> Spinal trigeminal nucleus

The reticular formation is a set of interconnected nuclei that are located in the brainstem, hypothalamus, and other regions. It is not anatomically well defined, because it includes neurons located in different parts of the brain. The neurons of the reticular formation make up a complex set of networks in the core of the brainstem that extend from the upper part of the midbrain to the lower part of the medulla oblongata. The reticular formation includes ascending pathways to the cortex in the ascending reticular activating system (ARAS) and descending pathways to the spinal cord via the reticulospinal tracts.

<span class="mw-page-title-main">Ventrolateral preoptic nucleus</span> Nucleus of the anterior hypothalamus

The ventrolateral preoptic nucleus (VLPO), also known as the intermediate nucleus of the preoptic area (IPA), is a small cluster of neurons situated in the anterior hypothalamus, sitting just above and to the side of the optic chiasm in the brain of humans and other animals. The brain's sleep-promoting nuclei, together with the ascending arousal system which includes components in the brainstem, hypothalamus and basal forebrain, are the interconnected neural systems which control states of arousal, sleep, and transitions between these two states. The VLPO is active during sleep, particularly during non-rapid eye movement sleep, and releases inhibitory neurotransmitters, mainly GABA and galanin, which inhibit neurons of the ascending arousal system that are involved in wakefulness and arousal. The VLPO is in turn innervated by neurons from several components of the ascending arousal system. The VLPO is activated by the endogenous sleep-promoting substances adenosine and prostaglandin D2. The VLPO is inhibited during wakefulness by the arousal-inducing neurotransmitters norepinephrine and acetylcholine. The role of the VLPO in sleep and wakefulness, and its association with sleep disorders – particularly insomnia and narcolepsy – is a growing area of neuroscience research.

Cataplexy is a sudden and transient episode of muscle weakness accompanied by full conscious awareness, typically triggered by emotions such as laughing, crying, or terror. Cataplexy affects approximately 20% of people who have narcolepsy, and is caused by an autoimmune destruction of hypothalamic neurons that produce the neuropeptide hypocretin, which regulates arousal and has a role in stabilization of the transition between wake and sleep states. Cataplexy without narcolepsy is rare and the cause is unknown.

Melanin-concentrating hormone (MCH), also known as pro-melanin stimulating hormone (PMCH), is a cyclic 19-amino acid orexigenic hypothalamic peptide originally isolated from the pituitary gland of teleost fish, where it controls skin pigmentation. In mammals it is involved in the regulation of feeding behavior, mood, sleep-wake cycle and energy balance.

<span class="mw-page-title-main">Endocannabinoid system</span> Biological system of neurotransmitters

The endocannabinoid system (ECS) is a biological system composed of endocannabinoids, which are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors, and cannabinoid receptor proteins that are expressed throughout the vertebrate central nervous system and peripheral nervous system. The endocannabinoid system remains under preliminary research, but may be involved in regulating physiological and cognitive processes, including fertility, pregnancy, pre- and postnatal development, various activity of immune system, appetite, pain-sensation, mood, and memory, and in mediating the pharmacological effects of cannabis. The ECS plays an important role in multiple aspects of neural functions, including the control of movement and motor coordination, learning and memory, emotion and motivation, addictive-like behavior and pain modulation, among others.

<span class="mw-page-title-main">Dorsomedial hypothalamic nucleus</span>

The dorsomedial hypothalamic nucleus is a nucleus of the hypothalamus. It is involved in feeding, drinking, body-weight regulation and circadian activity. More specifically, it is a necessary component for the expression of numerous behavioral and physiological circadian rhythms. The dorsomedial hypothalamic nucleus receives information from neurons and humors involved in feeding regulation, body weight and energy consumption, and then passes this information on to brain regions involved in sleep and wakefulness regulation, body temperature and corticosteroid secretion.

<span class="mw-page-title-main">Lateral hypothalamus</span>

The lateral hypothalamus (LH), also called the lateral hypothalamic area (LHA), contains the primary orexinergic nucleus within the hypothalamus that widely projects throughout the nervous system; this system of neurons mediates an array of cognitive and physical processes, such as promoting feeding behavior and arousal, reducing pain perception, and regulating body temperature, digestive functions, and blood pressure, among many others. Clinically significant disorders that involve dysfunctions of the orexinergic projection system include narcolepsy, motility disorders or functional gastrointestinal disorders involving visceral hypersensitivity, and eating disorders.

<span class="mw-page-title-main">Hypocretin (orexin) receptor 1</span> Protein-coding gene in the species Homo sapiens

Orexin receptor type 1 (Ox1R or OX1), also known as hypocretin receptor type 1 (HcrtR1), is a protein that in humans is encoded by the HCRTR1 gene.

<span class="mw-page-title-main">Hypocretin (orexin) receptor 2</span> Protein-coding gene in the species Homo sapiens

Orexin receptor type 2 (Ox2R or OX2), also known as hypocretin receptor type 2 (HcrtR2), is a protein that in humans is encoded by the HCRTR2 gene.

Orexin-A, also known as hypocretin-1, is a naturally occurring neuropeptide and orexin isoform. The orexinergic nucleus in the lateral hypothalamus is the primary orexin projection system in the brain.

<span class="mw-page-title-main">Narcolepsy</span> Human sleep disorder that involves an excessive urge to sleep and other neurological features

Narcolepsy is a chronic neurological disorder that involves a decreased ability to regulate sleep–wake cycles. Symptoms often include periods of excessive daytime sleepiness and brief involuntary sleep episodes. Narcolepsy paired with cataplexy is evidenced to be an autoimmune disorder. These experiences of cataplexy can be brought on by strong emotions. Less commonly, there may be vivid hallucinations or an inability to move while falling asleep or waking up. People with narcolepsy tend to sleep about the same number of hours per day as people without it, but the quality of sleep tends to be lessened.

<span class="mw-page-title-main">SB-334867</span> Chemical compound

SB-334867 is an orexin antagonist. It was the first non-peptide antagonist developed that is selective for the orexin receptor subtype OX1, with around 50x selectivity for OX1 over OX2 receptors. It has been shown to produce sedative and anorectic effects in animals, and has been useful in characterising the orexinergic regulation of brain systems involved with appetite and sleep, as well as other physiological processes. The hydrochloride salt of SB-334867 has been demonstrated to be hydrolytically unstable, both in solution and as the solid. Orexin antagonists have multiple potential clinical applications including the treatment of drug addiction, insomnia, obesity and diabetes.

<span class="mw-page-title-main">Suvorexant</span> Medication used to treat insomnia

Suvorexant, sold under the brand name Belsomra, is an orexin antagonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset and/or maintenance in adults. Suvorexant helps with falling asleep faster, sleeping longer, being awake less in the middle of the night, and having better quality of sleep. Its effectiveness is modest, and is similar to that of other orexin antagonists, but is lower than that of benzodiazepines and Z-drugs. Suvorexant is taken by mouth.

An orexin receptor antagonist, or orexin antagonist, is a drug that inhibits the effect of orexin by acting as a receptor antagonist of one (selective orexin receptor antagonist or SORA) or both (dual orexin receptor antagonis or DORA) of the orexin receptors, OX1 and OX2. Medical applications include treatment of sleep disorders such as insomnia.

<span class="mw-page-title-main">Seltorexant</span> Experimental anti-insomnia drug

Seltorexant, also known by its developmental code names MIN-202 and JNJ-42847922, is an orexin antagonist medication which is under development for the treatment of depression and insomnia. It is a selective antagonist of the orexin OX2 receptor (2-SORA). The medication is taken by mouth. As of February 2022, seltorexant is in phase 3 clinical trials for treatment of major depressive disorder (MDD) and phase 2 trials for treatment of insomnia. It was also under investigation for the treatment of sleep apnea, but no recent development has been reported for this indication. Seltorexant is under development by Minerva Neurosciences and Johnson & Johnson's Janssen Pharmaceuticals.

<span class="mw-page-title-main">Danavorexton</span> Chemical compound

Danavorexton is a selective orexin 2 receptor agonist. It is a small-molecule compound and is administered intravenously. The compound was found to dose-dependently produce wakefulness to a similar degree as modafinil in a phase 1 clinical trial. As of March 2021, danavorexton is under development for the treatment of narcolepsy, idiopathic hypersomnia, and sleep apnea. It is related to another orexin receptor agonist, firazorexton (TAK-994), the development of which was discontinued for safety reasons in October 2021.

<span class="mw-page-title-main">Masashi Yanagisawa</span> Japanese molecular biologist

Masashi Yanagisawa is a Japanese-American molecular biologist and physician, famous for his discovery of the hormone endothelin and the neuropeptide orexin, the absence of which is the cause of narcolepsy. He is currently the Director of the International Institute for Integrative Sleep Medicine, University of Tsukuba, and an adjunct professor at the Department of Molecular Genetics, University of Texas Southwestern Medical Center.

References

  1. ↑ de Lecea, L.; Kilduff, T.S.; Peyron, C.; Gao, X.-B.; Foye, P.E.; Danielson, P.E.; Fukuhara, C.; Battenberg, E.L.F.; Gautvik, V.T.; Bartlett II, F.S.; et al. (1998). "The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity". Proceedings of the National Academy of Sciences USA . 95 (1, number 1): 322–327. Bibcode:1998PNAS...95..322D. doi: 10.1073/pnas.95.1.322 . PMC   18213 . PMID   9419374.
  2. ↑ Sakurai, T.; Amemiya, A.; Ishii, M.; Matsuzaki, I.; Chemelli, R.M.; Tanaka, H.; Williams, S.C.; Richardson, J.A.; Kozlowski, G.P.; Wilson, S.; et al. (1998). "Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior". Cell . 92 (4, number 4): 573–585. doi: 10.1016/S0092-8674(00)80949-6 . PMID   9491897. S2CID   16294729.
  3. 1 2 3 "Our People: Thomas Kilduff". SRI International . Retrieved 2013-04-28.
  4. ↑ Thomas S. Kilduff; Ed S. Lein; Horacio de la Iglesia; Takeshi Sakurai; Ying-hui Fu & Paul Shaw (2008-11-12). "New Developments in Sleep Research: Molecular Genetics, Gene Expression, and Systems Neurobiology". The Journal of Neuroscience . 28 (46): 11814–11818. doi:10.1523/jneurosci.3768-08.2008. PMC   2628168 . PMID   19005045.
  5. ↑ Kilduff, T.S. & Peyron, C. (2000). "The hypocretin/orexin ligand-receptor system: Implications for sleep and sleep disorders". Trends in Neurosciences. 23 (8, number 8): 359–365. doi:10.1016/s0166-2236(00)01594-0. PMID   10906799. S2CID   37955645.
  6. ↑ "SRI International Research Team Identifies Rare Sleep-Activated Neurons in the Cerebral Cortex". SRI International. 2008-07-21. Retrieved 2013-06-15.
  7. ↑ Gerashchenko, D.; Wisor, J.P.; Burns, D.; Reh, R.K.; Shiromani, P.J.; Sakurai, T.; de la Iglesia, H.O. & Kilduff, T.S (2008). "Identification of a population of sleep-active cerebral cortex neurons". Proceedings of the National Academy of Sciences USA . 105 (29): 10227–10232. Bibcode:2008PNAS..10510227G. doi: 10.1073/pnas.0803125105 . PMC   2481371 . PMID   18645184.
  8. ↑ Kilduff, T.S.; Cauli, B. & Gerashchenko, D. (2011). "Activation of cortical interneurons during sleep: an anatomical link to homeostatic sleep regulation?". Trends in Neurosciences. 34 (1, number 1): 10–19. doi:10.1016/j.tins.2010.09.005. PMC   3014438 . PMID   21030095.
  9. 1 2 3 "SRI International Researcher Named American Association for the Advancement of Science (AAAS) Fellow". SRI International. 2010-01-20. Retrieved 2013-04-28.
  10. 1 2 "Stanford Scientist Thomas Kilduff Joins SRI International as Senior Program Director of Newly Formed Molecular Neurology Group". SRI International. 1999-01-25. Archived from the original on 2000-07-09. Retrieved 2013-04-28.
  11. 1 2 3 "Candidate: President Elect: Thomas Kilduff, PhD" (PDF). Sleep Research Society . Retrieved 2013-04-20.
  12. ↑ Kilduff TS, Bowersox SS, Faull KF, et al. (1987). "Modulation of activity of the striatal dopaminergic system during the hibernation cycle". Neuroscience . 7 (9): 2732–2736. doi: 10.1523/JNEUROSCI.07-09-02732.1987 . PMC   6569135 . PMID   3625271.
  13. ↑ Kilduff TS, Miller JD, Radeke CM, Sharp FR, Heller HC (1990). "14C-2-deoxyglucose uptake in the ground squirrel brain during entrance to and arousal from hibernation". Neuroscience . 10 (7): 2463–2475. doi: 10.1523/JNEUROSCI.10-07-02463.1990 . PMC   6570375 . PMID   2376782.
  14. ↑ Kilduff TS, Sharp FR, Heller HC (1982). "[14C]2-deoxyglucose uptake in ground squirrel brain during hibernation". Neuroscience . 2 (2): 143–157. doi: 10.1523/JNEUROSCI.02-02-00143.1982 . PMC   6564310 . PMID   6278102.
  15. ↑ Kilduff TS, Vugrinic C, Lee SL, et al. (1998). "Characterization of the circadian system of NGFI-A and NGFI-A/NGFI-B deficient mice". Journal of Biological Rhythms . 13 (4): 347–357. doi:10.1177/074873098129000174. PMID   9711509. S2CID   7759470.
  16. ↑ Sutin EL, Dement WC, Heller HC, Kilduff TS (1993). "Light-induced gene expression in the suprachiasmatic nucleus of young and aging rats". Neurobiology of Aging . 14 (5): 441–446. doi:10.1016/0197-4580(93)90102-H. PMID   8247226. S2CID   4044038.
  17. ↑ Sutin EL, Kilduff TS (1992). "Circadian and light-induced expression of immediate early gene mRNAs in the rat suprachiasmatic nucleus". Molecular Brain Research . 15 (3–4): 281–290. doi:10.1016/0169-328X(92)90119-V. PMID   1331682.
  18. ↑ Peyron, C.; Faraco, J.; Rogers, W.; Ripley, B.; Overeem, S.; Charnay, Y.; Nevsimalova, S.; Aldrich, M.; Reynolds, D.; Albin, R.; et al. (2000). "A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains". Nature Medicine . 6 (9, number 9): 991–997. doi:10.1038/79690. PMID   10973318. S2CID   18076282.
  19. ↑ Thannickal, T.; Moore, R.; Y., Nienhuis; R., Ramanathan; L., Gulyani; S., Aldrich; M., Cornford, M. & Siegel, J.M. (2000). "Reduced number of hypocretin neurons in human narcolepsy". Neuron . 27 (3, number 3): 469–474. doi: 10.1016/s0896-6273(00)00058-1 . PMC   8760623 . PMID   11055430. S2CID   5961605.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  20. ↑ "Fellows". American Association for the Advancement of Science . Retrieved 2013-04-28.
  21. ↑ "Distinguished Scientist Award". Sleep Research Society.
  22. ↑ "Thomas Kilduff". Frontiers. Retrieved 2013-07-28.
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