Understanding the Role of Increased Vessel Stiffness in Cell Death Associated with AMD

Kaustabh Ghosh, PhD
University of California, Riverside (Riverside, CA)
Year Awarded:
2016
Grant Duration:
July 1, 2016 to June 30, 2018
Disease:
Macular Degeneration
Award Amount:
$160,000
Grant Reference ID:
M2016161
Award Type:
Standard
Award Region:
US Southwestern

Micromechanical Determinants of Choriocapillaris Dysfunction in AMD Pathogenesis

Summary

Aging is an important risk factor for age-related macular degeneration (AMD). Aging is also associated with an increase in tissue stiffness. Yet, whether and how progressive tissue stiffening contributes to the worsening of this debilitating and degenerative eye disease remains unknown. The aim of this proposal is to address this gap in knowledge by using an innovative and interdisciplinary approach, so that new and potentially superior treatments can be developed to treat this condition in the future. 

Details

In this project, we are investigating the hypothesis that aging leads to stiffening of blood vessels in the eye that, in turn, exacerbates the pathogenesis of age-related macular degeneration (AMD) by causing inflammation-mediated vascular degeneration.

To test this hypothesis, we are using a rhesus monkey model of early AMD. Rhesus monkeys are a unique model for the study of AMD, as they have a retinal structure closely resembling that found in humans. They also share the same AMD risk genes with humans, and form drusen (cellular and protein debris accumulating at the back side of the eye) as seen in humans with early AMD.

For the first of the two specific aims, we are collecting eyes from three groups of rhesus monkeys: normal young animals with no drusen; old monkeys with no drusen; and age-matched old monkeys with severe drusen. The choroidal vessels, which lie at the back of the eye and undergo degeneration in early AMD, are being isolated for assessment of stiffness and extent of degeneration. Since early AMD is characterized by local inflammatory changes in the choroid, these measurements are being correlated with the expression of key inflammatory markers in these choroidal vessels.

For the second aim, we are examining the molecular pathways by which increased stiffness can promote inflammation-mediated degeneration of choroidal vessels. For these studies, we are isolating the endothelial cells (ECs) that form these choroidal vessels. As the isolated choroidal ECs can be readily manipulated in culture, they present a unique opportunity to study the role of intracellular molecular pathways in mediating choroidal vessel stiffness, inflammation, and degeneration.

Although AMD commonly causes blindness in the elderly, only 10-15 percent of all AMD patients who develop the advanced “wet” stage benefit from current therapies, while no therapies exist for the more prevalent “dry” form. Thus, there is an unmet need to better understand and treat early AMD. We believe our research is both innovative and unique in that our aim is to address this need by using a unique rhesus monkey model of early AMD that closely recapitulates the disease in humans. In contrast to the conventional focus on the role of genetic and biochemical risk factors in AMD, we are investigating a novel hypothesis that implicates age-related vessel stiffening in choroidal inflammation associated with early AMD. This hypothesis is inspired by recent work, by ourselves and others, that has revealed a crucial role of vascular stiffening in the pathogenesis of other inflammation-mediated vascular complications, including diabetic retinopathy, atherosclerosis, and pulmonary edema.

We believe that our novel hypothesis and multidisciplinary approach will not only illuminate a previously unexplored territory in AMD research but, crucially, also identify new stiffness-associated therapeutic targets for more effective AMD management in the future. Further, we envision that our use of bioengineering techniques can be readily extended to the study of other vision-threatening eye diseases, such as diabetic retinopathy, glaucoma, and retinal vein occlusion.

About the Researcher

Kaustabh Ghosh., PhD, is an assistant professor in the Department of Bioengineering, and the Cell, Molecular, and Developmental Biology Program at the University of California, Riverside (UCR). He is an interdisciplinary researcher with expertise in the fields of vascular inflammation, mechanobiology, bioengineering, and nanomedicine. Research in his lab aims to understand the often overlooked role of blood vessel stiffness in chronic inflammation associated with degenerative eye diseases such as age-related macular degeneration and diabetic retinopathy. Dr Ghosh has received several awards during his research career, including the Hellman Fellowship and an NIH Postdoctoral Training Grant, and has published 24 peer-reviewed papers in highly-regarded journals that include PNAS, The FASEB Journal, Science, and Nano Letters, among others. He currently serves as an editorial board member of the Journal of Regenerative Medicine and Tissue Engineering and a reviewer for several ophthalmology and bioengineering journals. Prior to joining UCR, he was a postdoctoral fellow in the Vascular Biology Program at Boston Children’s Hospital & Harvard Medical School. Dr Ghosh obtained his PhD in biomedical engineering in 2006 from SUNY at Stony Brook, where he received the President’s Award to Distinguished Doctoral Students.

Personal Story

While searching for an original idea to pursue as an independent researcher, I became interested in investigating the role of vessel stiffness in chronic inflammation, a major determinant of various debilitating conditions. My interest stemmed from the knowledge that although major risk factors for chronic vascular inflammation (such as diabetes and aging) have long been associated with increased blood vessel stiffness, the causal relationship between vascular stiffening and inflammation had not been examined. Another attractive aspect of this idea was that it deviates from conventional thinking that inflammation is governed solely by abnormal genetic and biochemical factors.

With this approach, I began to investigate the pathogenesis of early age-related macular degeneration (AMD), which is characterized by local inflammation and tissue atrophy (death) at the back side of the eye, and is considered to be a risk factor for the advanced stage of “wet” AMD. I was drawn to this condition because it remains very poorly understood and has enormous public health implications. Only 10-15 percent of all AMD patients who develop the advanced “wet” stage benefit from current therapies, while no therapies exist for the more prevalent early stage referred to as “dry” AMD. I hypothesized that age-related stiffening of the choroidal vessels in the back of the eye contributes to the inflammatory changes characteristic of early AMD.

This hypothesis represents an entirely new way of looking at an age-old problem. But to succeed, this idea needs adequate funding. However, many funding agencies are inclined to dismiss bold new ideas, especially from young investigators who are at an early stage of their career. I am, therefore, grateful to the entire BrightFocus Foundation community for the trust and confidence they have put in me and my research.

Publications

Cabrera AP, Bhaskaran A, Xu J, Yang X, Scott HA, Mohideen U, Ghosh K. Senescence Increases Choroidal Endothelial Stiffness and Susceptibility to Complement Injury: Implications for Choriocapillaris Loss in AMD. Invest Ophthalmol Vis Sci. 2016 Nov 1;57(14):5910-5918. doi: 10.1167/iovs.16-19727. PubMed PMID: 27802521. PubMed Icon Google Scholar Icon
 

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