Hélène Paradis

Development and Cancer to Ocular Health and Aging

Current treatments for several cancers rely heavily on chemotherapeutic approaches that can be highly toxic and unsuccessful. Treatments targeting more specific molecular targets are needed to decrease the toxicity and improve the quality of life of patients. One focus of our current research is to gain further insights into the signaling pathway and role of tubedown (TBDN or NAA15) in cancers. TBDN is a regulatory subunit of the mammalian acetyltransferase NAT1 (NAA10). Our group discovered and characterized its involvement in blood vessel development and vision health (Gendron et al., 2000; 2001; 2006; 2010; Wall et al., 2004; Paradis et al., 2002; 2008; Ho et al., 2015) However, we also found that TBDN is highly expressed in some pediatric cancers (see red staining in figure). TBDN could represent a target for designing new and improved treatments and could be a prognostic marker for specific childhood cancers (Martin et al., 2007; Nature Clinical Practice Oncology volume 4, pages 329–330, 2007).
	In retinal blood vessels, high levels of TBDN expression regulate a key blood vessel permeability pathway, preventing blood vessel hyperpermeability, overgrowth and retinal degeneration (Paradis et al., 2002; 2008; Gendron et al.,2010; Ho et al., 2015). TBDN levels in the retina are reduced in aged individuals and in blood vessels of patients with neovascular retinopathy including diabetic retinopathy, retinopathy of prematurity and age-related macular degeneration (Gendron et al., 2001; 2006; 2010). The TBDN regulatory pathway could possibly be a target for the design of new strategies to treat blindness involving neovascular retinopathy and retinal degeneration. Another of our researchobjectives is to test this in mouse models of neovascular retinopathy and retinal degeneration. In doing so, better treatments and improved quality of life may be realized for the millions of people world-wide afflicted with one of the forms of neovascular retinopathy.
Aging is associated with an increased rate of visual impairment. Cataract development is one of the main causes of vision loss in the elderly worldwide and in Newfoundland and Labrador. Surprisingly, there is very little information in the knowledge base on the development and prevention of cataract in humans. In a new research focus, my lab is utilizing the local resource ocean teleost Cyclopterus Lumpus (lumpfish), a visually guided predator fish, as a new model to study development of the visual system (Ahmad et al., 2019; Gendron et al., 2019) and natural cataract development (Paradis et al., 2019). This research focus is relevant both to cataract pathogenesis and treatment in humans as well as to the health and welfare of the lumpfish of the Northwest Atlantic.

BIOGRAPHICAL INFORMATION:

Doctorate: 1991, University of Montreal, Molecular Biology.

Post-Doctoral Training: 1991-1994, Harvard Medical School, Dana Farber Cancer Institute, Signal Transduction.

RELEVANT PUBLICATIONS:

Tubedown-1, a novel acetyltransferase associated with blood vessel development. Gendron RL, Adams LC, Paradis H. Dev Dyn. 2000 Jun;218(2):300-15.

Suppressed expression of tubedown-1 in retinal neovascularization of proliferative diabetic retinopathy. Gendron RL, Good WV, Adams LC, Paradis H. Invest Ophthalmol Vis Sci. 2001 Nov;42(12):3000-7.

Tubedown-1 in remodeling of the developing vitreal vasculature in vivo and regulation of capillary outgrowth in vitro. Paradis H, Liu CY, Saika S, Azhar M, Doetschman T, Good WV, Nayak R, Laver N, Kao CW, Kao WW, Gendron RL. Dev Biol. 2002 Sep 1;249(1):140-55.

Conditional knockdown of tubedown-1 in endothelial cells leads to neovascular retinopathy. Wall DS, Gendron RL, Good WV, Miskiewicz E, Woodland M, Leblanc K, Paradis H. Invest Ophthalmol Vis Sci. 2004 Oct;45(10):3704-12.

Tubedown-1 (Tbdn-1) suppression in oxygen-induced retinopathy and in retinopathy of prematurity. Gendron RL, Good WV, Miskiewicz E, Tucker S, Phelps DL, Paradis H. Mol Vis. 2006 Feb 22;12:108-16.

Tubedown expression correlates with the differentiation status and aggressiveness of neuroblastic tumors. Martin DT, Gendron RL, Jarzembowski JA, Perry A, Collins MH, Pushpanathan C, Miskiewicz E, Castle VP, Paradis H. Clin Cancer Res. 2007 Mar 1;13(5):1480-7.

Tubedown expression is a novel independent prognostic factor for neuroblastoma. Nature Clinical Practice Oncology 2007; 4, 329-30.

Tubedown associates with cortactin and controls permeability of retinal endothelial cells to albumin. Paradis H, Islam T, Tucker S, Tao L, Koubi S, Gendron RL. J Cell Sci. 2008 Jun 15;121(Pt 12):1965-72. doi: 10.1242/jcs.028597.

Loss of tubedown expression as a contributing factor in the development of age-related retinopathy. Gendron RL, Laver NV, Good WV, Grossniklaus HE, Miskiewicz E, Whelan MA, Walker J, Paradis H. Invest Ophthalmol Vis Sci. 2010 Oct;51(10):5267-77. doi: 10.1167/iovs.09-
4527.

Tubedown regulation of retinal endothelial permeability signaling pathways. Ho N, Gendron RL, Grozinger K, Whelan MA, Hicks EA, Tennakoon B, Gardiner D, Good WV, Paradis H. Biol Open. 2015 Jul 3;4(8):970-9. doi: 10.1242/bio.010496.

Novel characteristics of the cultured Lumpfish Cyclopterus lumpus eye during post-hatch larval and juvenile developmental stages. Ahmad R, Paradis H, Boyce D, McDonald J, Gendron RL. J Fish Biol. 2019 Feb;94(2):297-312. doi: 10.1111/jfb.13892.

Lumpfish eye sight in the context of fish farming. Gendron RL, Ahmad R, Paradis H. Fish Farmer Magazine (May 2019), United Kingdom, 84-85. https://issuu.com/fishfarmermagazine/docs/fish_farmer_may_2019

Ocular tissue changes associated with anterior segment opacity in lumpfish (Cyclopterus lumpus L) eye. Paradis H, Ahmad R, McDonald J, Boyce D, Gendron RL. J Fish Dis. 2019 Oct;42(10):1401-1408. doi: 10.1111/jfd.13065.