Neuronal Control of IOP

Krishnakumar Kizhatil, PhD
The Jackson Laboratory (Bar Harbor, ME)

Collaborators

Simon W. M. John, PhD
The Jackson Laboratory (Bar Harbor, ME)
Year Awarded:
2017
Grant Duration:
July 1, 2017 to June 30, 2019
Disease:
Glaucoma
Award Amount:
$150,000
Grant Reference ID:
G2017152
Award Type:
Standard
Award Region:
US Northeastern
Krishnakumar Kizhatil, PhD

Determining the Neuronal Control of IOP

Summary

Glaucoma is a devastating neurodegenerative disease that causes blindness. Glaucoma results from increased pressure in the eye; however, the mechanistic basis of the pressure increase is largely undetermined. Neurons innervating the eye play a role in controlling pressure, but again the specific mechanisms are not clear. We will determine the mechanistic basis of neuronal control of eye pressure using mice and modern imaging and molecular methods.

Details

The objective of my proposal is to determine how neuronal control regulates aqueous humor (AQH) outflow and intraocular pressure (IOP). Glaucoma is a common blinding disease affecting over 70 million people. High IOP is a causal risk factor for glaucoma. Abnormally increased resistance to AQH drainage elevates IOP in glaucoma. The nervous system is important in controlling AQH drainage and hence IOP regulation. However, despite several previous studies, the precise mechanisms by which the nervous system controls IOP remain unclear. Historically, this was an intense field of study; however, contemporary research in this field has been few and far between. I will revisit how IOP is regulated by the nervous system using fluorescent transgenic mice, modern neurobiological techniques and unique and innovative tools we have developed to study the neuronal control of AQH drainage. This study will revitalize an understudied area of IOP and glaucoma research.

 In Specific Aim 1, we will determine the nature and patterning of limbal innervation. We will construct a detailed 3-dimensional (3D) map of the neuronal innervation of the AQH drainage structures by imaging either fluorescent protein-expressing neurons, or a subtype with specific neuronal immunolabeling, using high-resolution confocal microscopy and 3D reconstruction of whole-mounts of the anterior segment of mouse eyes. In Specific Aim 2, we will find out if experimental manipulation of IOP activates the neurons innervating the drainage structures. IOP activation of neurons will be determined in mice expressing neuronal activation reporters using high-resolution microscopy. Finally, in Specific Aim 3, we will test the functional contribution of the neurons in control of IOP and outflow using drugs that specifically inhibit various classes of neurons, combined with a novel physiological technique to measure outflow. These foundational studies will lay the groundwork for a more comprehensive study aimed at determining the precise mechanisms of IOP regulation by the nervous system.

The molecular basis for the primary risk factor for glaucoma, elevation of IOP, is largely undetermined. This is a critical field of study because the current drug therapies to lower IOP often are minimally effective and have unpleasant side effects. Surgery often becomes necessary to lower IOP as the disease progresses. Surgery carries risks for the patient, including possible vision loss, bleeding, low eye pressure, scarring, and cataracts; and often the IOP lowering effect of surgery is lost after only a few years. There is a pressing need for more effective therapies with lesser side effects; however, this means identifying the factors controlling IOP more precisely. Our foundational experiments funded by the BrightFocus grant will be used as a platform to study the neuronal control of IOP using modern techniques with the hope of developing novel glaucoma treatments.

About the Researcher

Dr. Kizhatil is an associate research scientist at The Jackson Laboratory. Dr. Kizhatil earned a PhD in microbiology and immunology at the University of Tennessee, Memphis, where he uncovered a new role for the cellular cytoskeleton in murine retrovirus entry. Using his initial finding as a template, other groups have found a requirement for the cellular cytoskeleton in entry of other retroviruses, including HIV. This early work was followed by postdoctoral studies at Duke University, where he identified a novel and conserved role for the membrane skeletal protein ankyrin in post-Golgi delivery of membrane proteins to the plasma membrane in epithelial cells and photoreceptors. Dr. Kizhatil has been an extremely productive scientist and has published several high-quality papers in peer-reviewed journals during both his graduate work as well as postdoctoral studies. At The Jackson Laboratory, he works closely with Dr. Simon John, a leading glaucoma researcher.

Dr. Kizhatil’s research is focused on identifying molecular pathways regulating intraocular pressure (IOP) elevation, a major risk factor for glaucoma. His studies have shown that Schlemm’s canal (SC) which is central in ocular fluid homeostasis, hence IOP, and thus is directly relevant to glaucoma, has a novel, specialized phenotype with properties that are a blend of blood and lymphatic endothelia based on expression of marker proteins of each lineage. His work also has made important advances in resolving a decade's old controversy about the developmental origins and developmental sequence of the SC. The paper describing these findings was honored with the Lewis Rudin Glaucoma Prize in 2015.     

Personal Story

I thank the donors of BrightFocus Foundation for supporting my project.  My expectation and hope is that the findings from this study will help aid rational design of better drugs for the treatment of glaucoma. It is a great honor to be included among the ranks of all the excellent scientists supported by BrightFocus Foundation and be part of this community.

I became an eye researcher completely by accident while trying to unravel the role of a protein called Ankyrin in forming biological important membrane domains in cells, in this case, the photoreceptor. It was just a model system, to begin with until I came into contact with patients in the clinic with visual challenges. Seeing their struggles, I became motivated to do something to help these patients. At about this time some family members were directly affected by vision challenges due to glaucoma.  Serendipitously, I was recruited by Simon John, a pioneering glaucoma researcher at the Jackson Laboratory. My overarching goal in the lab is to determine the molecular basis of intraocular pressure and ultimately find targets that can be used to design therapies for glaucoma. I find the challenges of this study fascinating and the fact that I in some measure would contribute to mitigating the suffering of a fellow human being inspiring.  

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