Dr. Caldwell’s research, supported by grants from the NIH, VA and the AHA, seeks to elucidate the cellular and molecular mechanisms of retinal neurovascular injury and pathological angiogenesis in order to identify new therapies to limit damage and promote repair. Current studies seek to determine the specific role of the urea and ornithine generating metallo-enzyme arginase in retinal neurovascular injury and repair and to develop therapies targeting this enzyme and its downstream targets. Studies are also underway to develop new therapies targeting retinal cholesterol metabolism as a therapy for retinopathy of prematurity.
The arginase enzyme: Scheme for the catabolism of l-arginine to l -ornithine/urea or l-citrulline/NO, production of polyamines and anabolism and catabolism of proline. Also shown are the pathway for synthesis of l-arginine from l-glutamine, the reversible pathway between l-ornithine and l-glutamine, and the recycling of l-citrulline into l-arginine. ASL, argininosuccinate lyase; ASS, argininosuccinate synthase; NOS, nitric oxide synthase; OAT; ornithine aminotransferase; ODC, ornithine decarboxylase; OTC, ornithine transcarbamylase. Arginase (top left) is the final enzyme in the urea cycle within the liver, which restarts the cycle through the synthesis of l-citrulline from carbamoyl-phosphate (1) and l-ornithine (2) by OTC (middle). It should be noted that not all of these reactions occur within a given cell. In particular, the urea cycle is independent of the other reactions, i.e., l-arginine produced in the urea cycle is not a substrate for NOS and l-ornithine produced in the urea cycle is not a substrate for OAT or ODC.
Figure and description are from our recent article in ‘Physiological Reviews’:
Arginase: A Multifaceted Enzyme Important in Health and Disease. R. William Caldwell, Paulo C. Rodriguez, Haroldo A. Toque, S. Priya Narayanan, and Ruth B. Caldwell. 07 FEB 2018https://doi.org/10.1152/physrev.00037.2016
We have various ongoing projects investigating the role of the arginase pathway in different retinal pathology models. The models we use in lab include mouse models of diabetic retinopathy (Akita mice and STZ models of type 1 diabetes, as well as the high fat diet induced obesity model of type 2 diabetes), traumatic optic neuropathy (TON), retinal ischemia-reperfusion (IR) injury, and oxygen-induced retinopathy (OIR) model. Our lab has extensive expertise in these disease models. We utilize different biochemical, molecular, and histological assays as well as different retinal functional and imaging analyses to examine retinal neurovascular injury.
Liu Z, Xu J, Ma Q, Zhang X, Yang Q, Wang L, Cao Y, Xu Z, Tawfik A, Sun Y, Weintraub NL, Fulton DJ, Hong M, Dong Z, Smith LEH, Caldwell RB, Sodhi A, Huo Y. Glycolysis links reciprocal activation of myeloid cells and endothelial cells in the retinal angiogenic niche. Sci Transl Med. 2020 Aug 5;12(555).
Atawia RT, Bunch KL, Fouda AY, Lemtalsi T, Eldahshan W, Xu Z, Saul A, Elmasry K, Al-Shabrawey M, Caldwell RB, Caldwell RW. Role of arginase 2 in murine retinopathy associated with western diet-induced obesity . J Clin Med. 2020 Jan 22;9(2).
Liu F, Saul AB, Pichavaram P, Xu Z, Rudraraju M, Somanath PR, Smith SB, Caldwell RB, Narayanan SP. Pharmacological inhibition of spermine oxidase reduces neurodegeneration and improves retinal function in diabetic mice. J Clin Med. 2020 Jan 25;9(2). doi: 10.3390/jcm9020340. PubMed PMID: 31991839; PubMed Central PMCID: PMC7074464.
Shosha E, Fouda AY, Narayanan SP, Caldwell RW, Caldwell RB. Is the arginase pathway a novel therapeutic avenue for diabetic retinopathy? J Clin Med. 2020 Feb 5;9(2).
Fouda AY, Xu Z, Narayanan SP, Caldwell RW, Caldwell RB. Utility of LysM-cre and Cdh5-cre driver mice in retinal and brain research: An imaging study using tdTomato reporter mouse. Invest Ophthalmol Vis Sci. 2020 Mar 9;61(3):51. doi: 10.1167/iovs.61.3.51.
Fouda AY, Eldahshan W, Narayanan SP, Caldwell RW, Caldwell RB. Arginase pathway in acute retina and brain injury: Therapeutic opportunities and unexplored avenues. Front Pharmacol. 2020;11:277.
Palani CD, Fouda AY, Liu F, Xu Z, Mohamed E, Giri S, Smith SB, Caldwell RB, Narayanan SP. Deletion of Arginase 2 Ameliorates Retinal Neurodegeneration in a Mouse Model of Multiple Sclerosis. Mol Neurobiol. 2019 Jul 6. doi: 10.1007/s12035-019-01691-w. [Epub ahead of print]
Lv H, Zhu C, Wu R, Ni H, Lian J, Xu Y, Xia Y, Shi G, Li Z, Caldwell RB, Caldwell RW, Yao L, Chen Y. Chronic mild stress induced anxiety-like behaviors can be attenuated by inhibition of NOX2-derived oxidative stress. J. Psych Res. Apr 23;114:55-66
Atawia RT, Bunch KL, Toque HA, Caldwell RB, Caldwell RW. Mechanisms of obesity-induced metabolic and vascular dysfunctions. Front Biosci (Landmark Ed). 2019 Mar 1;24:890-934.
Atawia RT, Toque HA, Meghil MM, Benson TW, Yiew NKH, Cutler CW, Weintraub NL, Caldwell RB, Caldwell RW. Role of arginase 2 in systemic metabolic activity and adipose tissue fatty acid metabolism in diet-induced obese mice. Int J Mol Sci. 2019 Mar 22;20(6). pii: E1462.
Complete List of Published Work in MyBibliography: