Marijan Farid, MD; Department of Ophthalmology
M. Cristina Kenney, M.D., Ph.D.; Department of Ophthalmology
Albert F. Yee, Ph.D.; Department of Chemical Engineering
The goal of the proposed research is to design and imprint topographical nanostructures on the surface of polymethylmethacrylate (PMMA) to control cell adhesion to produce the effects needed for a successful artificial cornea constructed entirely from PMMA, which is an FDA-approved material. This interdisciplinary collaboration, our team plans to develop geometries and dimensions for nanopatterns on the surface of PMMA that simultaneously repel micro-organisms that could cause infection and enhance the adhesion of fibroblasts to the surface.The proposed research promises to produce advances that are innovative and important at both scientific and clinical levels. Corneal opacity is the second most common cause of blindness in the world despite corneal transplant surgery, due either to rejection and failure of human tissue transplants, or due to obstacles to the use of fresh tissue transplants in some parts of the world. Artificial corneal transplants (keratoprosthesis) can restore vision to these patients, but intensive postoperative medical care is required to reduce the loss of the keratoprosthesis due to infection or tissue breakdown. Our team proposes to use physical surface nanotopography to resolve issues associated with current keratoprostheses
The neuropeptide oxytocin (OXT) has been implicated in the etiology of autism based on its criticalinvolvement in social recognition, social bonding, parental care and other forms of prosocial behavior inanimals (6, 7). Indeed, OXT pathways and oxytocin receptors are known to play important roles in thesocial brain throughout evolution (8). Oxytocin is produced mainly in the large magnocellular neuronsof the supraoptic and paraventricular nuclei in the hypothalamus, sending axons to the posteriorpituitary, where OXT is released into the bloodstream to produce its peripheral effects (9). At the sametime, OXT is released diffusely from the dendrites of these cells (and also from axon collaterals) toseveral forebrain limbic structures, including the olfactory bulb (to increase social recognition), nucleusaccumbens (to increase social reward) and amygdala (to decrease social anxiety) (9). Such simultaneouscentral and peripheral release of OXT – which may serve to coordinate its central and peripheralactivities – also makes it plausible to assume that plasma OXT reflects in some measure the central toneof this neuropeptide. How else might one explain the ever-increasing body of reports that demonstrate arelationship between plasma OXT and behavior (10)?
Comparative studies in field rodents reveal the special role of oxytocin receptors (OXTR) in speciesspecificsocial behavior (6, 7). Prairie voles are socially monogamous; males and females form longtermpair bonds, establish a nest site and rear their offspring together. In contrast, meadow voles do not2form a bond with a mate and only the females take part in rearing the young. Very high levels of OXTRare localized in the nucleus accumbens and caudate putamen of monogamous prairie voles, whereassignificantly lower densities of OXTR are found in the same brain regions of polygamous meadowvoles. Such species-specific correlation of forebrain OXTR with monogamy and other prosocial behaviorsis compelling, and it is supported by many related genetic and pharmacological observations (11).These and other considerations have led investigators to postulate an oxytocin-autism hypothesis, whichwe may state as follows: OXT brain pathways are thought to be developmentally disordered in autism,largely as a result of polygenetic mutations, and thereby give rise to a variety of cognitive andbehavioral social deficits. But what, precisely, is the hypothesized brain oxytocin disorder in ASD? Isit insufficient release of OXT transmitter? Or is it subsensitivity of oxytocin receptors? In analogy withdiabetes, a deficit in oxytocin release might be termed “Type I” ASD and a deficit in receptor sensitivitymight be termed “Type II” ASD. It is also possible that both problems are present in ASD individuals.
Human studies reveal a significant depression of serum OXT in autistic children and young adults (12,13). In addition, in neurotypical children, serum OXT levels correlate positively with social skill (10).These facts are consistent with the transmitter insufficiency hypothesis. But paradoxically, in autisticsubjects, the correlation between plasma OXT and social skill is actually negative; and furthermore, thisnegative correlation is much greater in severely-affected than in mildly-affected ASD subgroups (12).The unexpected and puzzling observation of a negative correlation between OXT and social acuitymeans that the autistic children with the most normal oxytocin levels have the worst social phenotype.Hammock and Young (6), leading proponents of the oxytocin-autism hypothesis, comment on thenegative correlation as follows: “This makes the data difficult to interpret and the potential role ofoxytocin in the aetiology of autism very unclear” (p. 2194).
We interpret the negative correlation between OXT and social skill in autistic children differently. We suggest instead that the apparently paradoxical negative correlation of Modahl et al. (12) is an excitingfinding, which specifically favors the receptor subsensitivity hypothesis over the release insufficiencyhypothesis. We hypothesize on homeostatic grounds that OXTR subsensitivity will inducecompensatory increases in oxytocin release, and that the severely-affected autistic subjects –presumably, those suffering the greatest OXTR deficits – will overcompensate and thus will releasemore oxytocin into their bloodstream and brains than mildly-affected subjects.The OXTR subsensitivity hypothesis explains a second critical fact, which refers to the apparentineffectiveness of oxytocin as a long-term autism treatment (14). Although large and well-controlledclinical trials of OXT in autism are still lacking, the absence of papers reporting lasting gains after somany years of speculation about OXT’s therapeutic potential suggests that OXT treatments in fact arelargely ineffective as an intervention for ASD. Of course, if oxytocin receptors were pathologicallyinsensitive in autism, applications of OXT or OXT agonists would not be expected to be effective as along-term treatment – even if, upon acute administration, oxytocin may briefly ameliorate specificautistic symptoms (e.g., 13). By analogy, although amphetamine is contraindicated as an interventionfor depression, acute doses of the drug sometimes produce a brief elevation of mood.
Mutations of the OXTR gene on chromosome 3 have been reported to be associated with autism inseveral studies (15-17), but a failure to replicate these findings has also been reported (18). In a wellcharacterizedcase, Gregory et al. (17) found a deletion in chromosome 3 that essentially knocked outOXTR both in an autistic boy and his obsessive-compulsive but non-autistic mother. In the samefamily, an autistic brother of the proband did not have the OXTR deletion, but instead had epigeneticsilencing of his OXTR gene through DNA methylation. These observations of Gregory et al. (17)support the OXTR-autism hypothesis, but they remind us again that the etiology of autism is polygenetic3and gender-dependent. In complex polygenetic disorders like ASD, the failure to replicate a specificrisk factor of small effect may be the rule, since such genes are unlikely to be pathological bythemselves but only in unfortunate combination with a particular set of others.
Thus, while OXTR gene mutations might cause autism in occasional cases, we think that ASD moretypically may involve dysfunctional mechanisms of OXTR desensitization and downregulation,disordered OXTR trafficking, and the probable loss of receptor protein. Like virtually all other Gprotein-coupled receptors, OXTRs undergo a multistep process upon agonist stimulation in which theylose their ability to respond for varying lengths of time (19). Desensitization refers to the relativelyrapid loss of receptor function after brief agonist exposure and involves receptor phosphorylation,recruitment of β-arrestin, and internalization of the receptor. The internalized OXTRs are targeted todifferent intracellular compartments, where their subsequent fate is determined. In one trafficking mode(resensitization), the OXTR molecules are stripped of their agonist, β-arrestin and phosphate and arerapidly recycled back to the plasma membrane with their sensitivity restored. There is negligible loss ofreceptor protein in this mode.
In contrast, downregulation refers to the significant loss of receptor protein following prolongedtreatment with the agonist. Loss of receptors occurs when the internalized receptors are transported tolysosomes where they are degraded; on a probabilistic basis, longer durations of agonist exposure andreceptor internalization will favor this irreversible mode of trafficking. As noted, severely-affectedautistic children had higher serum (and presumably brain) OXT levels than their moderately-affectedcounterparts (12); hence, in severe forms of ASD, the autistic subject will be chronically exposed tomore OXT stimulation than in mild forms. But OXT overexposure is a long-established recipe forpreferential induction of OXTR downregulation at the expense of OXTR resensitization (20). MightASD thus involve a vicious circle consisting, perhaps, of oxytocin exposure causing OXTRdesensitization causing excessive compensatory OXT release causing OXTR downregulation…? Andmight this hypothetical vicious circle arise from still-to-be-identified genetic and epigenetic factors?
Anthony Durkin PhD; Department of Suregry
Kristin Kelly, MD; Department of Dermatology
Vasan Venugopalan Sc.D; Department of Chemical Engineering & Materials Science
This project will yield a compact, handheld optical device for non-invasive diagnosis of melanoma that can be easily carried between clinical locations in which patients with pigmented lesions are commonly seen, including the UC Irvine Cancer Center, Gottschalk Medical Plaza and the Medical Clinic at the Beckman Laser Institute (BLI). The proposed technology has been developed, but is currently too large and fragile to be moved between locations. Hence, we are limited in our efforts to collect meaningful in-vivo data in order to complete development and testing of this potentially impactful skin cancer (Melanoma) screening technique.