About My Research
Center/Research Area Affiliations
Biography
Dr. Gregory-Ksander has a longstanding interest in how age-related changes in immune privilege and subsequent inflammation contributes to the development of ocular disease. The current research in Dr. Gregory-Ksander’s lab at Schepens Eye Research Institute at Mass. Eye and Ear is specifically focused on how age-related changes in immune privilege and subsequent inflammation contributes to the development of glaucoma and age-related macular degeneration (AMD). Using animal models of glaucoma and AMD, Dr. Gregory-Ksander has identified Fas ligand (FasL) and the NLRP3 inflammasoma as two critical mediators of ocular inflammation and current studies focus on how age-related changes in FasL and the NLRP3 inflammasome contribute to the development of inflammation associated with glaucoma and AMD.
- Loss of epigenetic information as a cause of mammalian aging. Cell. 2024 Feb 29; 187(5):1312-1313.
- The Role of Complement Dysregulation in Glaucoma. Int J Mol Sci. 2024 Feb 15; 25(4).
- Sustained Vision Recovery by OSK Gene Therapy in a Mouse Model of Glaucoma. Cell Reprogram. 2023 12; 25(6):288-299.
- Staphylococcus aureus activates NRLP3-dependent IL-1ß secretion from human conjunctival goblet cells using a toxin and toll-like receptors 2 and 1. Front Cell Infect Microbiol. 2023; 13:1265471.
- Loss of epigenetic information as a cause of mammalian aging. Cell. 2023 01 19; 186(2):305-326.e27.
- Microglia depletion exacerbates retinal ganglion cell loss in a mouse model of glaucoma. Exp Eye Res. 2022 12; 225:109273.
- Cell Death in AMD: The Rationale for Targeting Fas. J Clin Med. 2022 Jan 25; 11(3).
- Targeting the NLRP3 Inflammasome in Glaucoma. Biomolecules. 2021 08 19; 11(8).
- The FasLane to ocular pathology-metalloproteinase cleavage of membrane-bound FasL determines FasL function. J Leukoc Biol. 2021 11; 110(5):965-977.
- Reprogramming to recover youthful epigenetic information and restore vision. Nature. 2020 12; 588(7836):124-129.
- A small peptide antagonist of the Fas receptor inhibits neuroinflammation and prevents axon degeneration and retinal ganglion cell death in an inducible mouse model of glaucoma. J Neuroinflammation. 2019 Sep 30; 16(1):184.
- Mouse model of ocular hypertension with retinal ganglion cell degeneration. PLoS One. 2019; 14(1):e0208713.
- Soluble Fas ligand blocks destructive corneal inflammation in mouse models of corneal epithelial debridement and LPS induced keratitis. Exp Eye Res. 2019 02; 179:47-54.
- Increased bioavailability of cyclic guanylate monophosphate prevents retinal ganglion cell degeneration. Neurobiol Dis. 2019 01; 121:65-75.
- Neither non-toxigenic Staphylococcus aureus nor commensal S. epidermidi activates NLRP3 inflammasomes in human conjunctival goblet cells. BMJ Open Ophthalmol. 2017; 2(1):e000101.
- Overexpression of Soluble Fas Ligand following Adeno-Associated Virus Gene Therapy Prevents Retinal Ganglion Cell Death in Chronic and Acute Murine Models of Glaucoma. J Immunol. 2016 12 15; 197(12):4626-4638.
- ABCB5 is a limbal stem cell gene required for corneal development and repair. Nature. 2014 Jul 17; 511(7509):353-7.
- Staphylococcus aureus activates the NLRP3 inflammasome in human and rat conjunctival goblet cells. PLoS One. 2013; 8(9):e74010.
- Increased resistance to Staphylococcus aureus endophthalmitis in BALB/c mice: Fas ligand is required for resolution of inflammation but not for bacterial clearance. Infect Immun. 2013 Jun; 81(6):2217-25.
- Soluble Guanylate Cyclase a1-Deficient Mice: a novel murine model for Primary Open Angle Glaucoma. Ann Neurosci. 2013 Apr; 20(2):65-6.
- Soluble guanylate cyclase a1-deficient mice: a novel murine model for primary open angle glaucoma. PLoS One. 2013; 8(3):e60156.
- NLRP3 inflammasome activation in retinal pigment epithelial cells by lysosomal destabilization: implications for age-related macular degeneration. Invest Ophthalmol Vis Sci. 2013 Jan 07; 54(1):110-20.
- Ocular inflammation and infection. Int J Inflam. 2012; 2012:403520.
- Opposing roles for membrane bound and soluble Fas ligand in glaucoma-associated retinal ganglion cell death. PLoS One. 2011 Mar 29; 6(3):e17659.
- Spontaneous bacterial keratitis in CD36 knockout mice. Invest Ophthalmol Vis Sci. 2011 Jan; 52(1):256-63.
- alphaB-crystallin protects retinal tissue during Staphylococcus aureus-induced endophthalmitis. Infect Immun. 2008 Apr; 76(4):1781-90.
- Control of ocular tumor growth and metastatic spread by soluble and membrane Fas ligand. Cancer Res. 2007 Dec 15; 67(24):11951-8.
- Bacterial endophthalmitis: therapeutic challenges and host-pathogen interactions. Prog Retin Eye Res. 2007 Mar; 26(2):189-203.
- Role of bacterial and host factors in infectious endophthalmitis. Chem Immunol Allergy. 2007; 92:266-275.
- A novel treatment for ocular tumors using membrane FasL vesicles to activate innate immunity and terminate immune privilege. Invest Ophthalmol Vis Sci. 2005 Jul; 46(7):2495-502.
- In vivo gene delivery and visualization of corneal stromal cells using an adenoviral vector and keratocyte-specific promoter. Invest Ophthalmol Vis Sci. 2004 Jul; 45(7):2194-200.
- Effect of acute ethanol exposure on the dermal inflammatory response after burn injury. Alcohol Clin Exp Res. 2003 Jul; 27(7):1199-206.
- By altering ocular immune privilege, bone marrow-derived cells pathogenically contribute to DBA/2J pigmentary glaucoma. J Exp Med. 2003 May 19; 197(10):1335-44.
- Elevated monocyte chemoattractant protein-1 levels following thermal injury precede monocyte recruitment to the wound site and are controlled, in part, by tumor necrosis factor-alpha. Wound Repair Regen. 2003 Mar-Apr; 11(2):110-9.
- Membrane Fas ligand activates innate immunity and terminates ocular immune privilege. J Immunol. 2002 Sep 01; 169(5):2727-35.
- Estrogen regulation of immune responses after injury. Mol Cell Endocrinol. 2002 Jul 31; 193(1-2):129-35.
- Survival and cell mediated immunity after burn injury in aged mice. J Am Aging Assoc. 2002 Jan; 25(1):3-9.
- Fas ligand engagement of resident peritoneal macrophages in vivo induces apoptosis and the production of neutrophil chemotactic factors. J Immunol. 2001 Dec 01; 167(11):6217-24.
- Differential production of prostaglandin E(2) in male and female mice subjected to thermal injury contributes to the gender difference in immune function: possible role for 15-hydroxyprostaglandin dehydrogenase. Cell Immunol. 2000 Nov 01; 205(2):94-102.
- The role of interleukin 6 in interferon-gamma production in thermally injured mice. Cytokine. 2000 Nov; 12(11):1669-75.
- Anti-interleukin-6 antibody treatment restores cell-mediated immune function in mice with acute ethanol exposure before burn trauma. Alcohol Clin Exp Res. 2000 Sep; 24(9):1392-9.
- Gender difference in cell-mediated immunity after thermal injury is mediated, in part, by elevated levels of interleukin-6. J Leukoc Biol. 2000 Mar; 67(3):319-26.
- Estrogen mediates the sex difference in post-burn immunosuppression. J Endocrinol. 2000 Feb; 164(2):129-38.
- Neutrophil chemokine production in the skin following scald injury. Burns. 1999 Aug; 25(5):403-10.
- Elevation in pulmonary neutrophils and prolonged production of pulmonary macrophage inflammatory protein-2 after burn injury with prior alcohol exposure. Am J Respir Cell Mol Biol. 1999 Jun; 20(6):1229-37.
- Glucocorticoids protect against suppression of T cell responses in a murine model of acute ethanol exposure and thermal injury by regulating IL-6. J Leukoc Biol. 1998 Dec; 64(6):724-32.
- Acute ethanol exposure prior to thermal injury results in decreased T-cell responses mediated in part by increased production of IL-6. Shock. 1998 Aug; 10(2):135-40.
- Effects of acute ethanol exposure on cellular immune responses in a murine model of thermal injury. J Leukoc Biol. 1997 Dec; 62(6):733-40.
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Fas Ligand as a target for neuroprotection in Glaucoma
In 2003 Dr. Gregory-Ksander made the first connection between the form of FasL (membrane (mFasL) or soluble (sFasL)) and the pathogenesis of glaucoma in DBA/2J mice (spontaneous mouse model of glaucoma). Working in collaboration with Dr. Simon John at The Jackson Laboratory in Bar Harbor, ME. Dr. Gregory-Ksander demonstrated that ocular immune privilege was terminated in DBA/2J mice prior to the development of glaucoma. Dr. Gregory-Ksander went on to demonstrate that the development of glaucoma also coincided with increased expression of mFasL in the eye.
To further examine the role of mFasL and sFasL in ocular homeostasis and glaucoma, Dr. Gregory-Ksander, in collaboration with Dr. Ann Marshak-Rothstein at University Massachusetts School of Medicine in Worcester, constructed a membrane-only FasL gene-targeted mouse in which the FasL metalloproteinase cleavage sites were mutated. These mice only express mFasL and no sFasL. Using these mice in an inducible and spontaneous model of glaucoma Dr. gregroy-Ksander was able to specifically address how membrane and soluble forms of FasL contribute to the development of glaucoma.
The results of these studies were significant because they:
- Elucidated the mechanism of retinal ganglion cell and nerve fiber destruction in glaucoma
- Identified cleavage of the FasL molecule as a major mechanism controlling FasL activity in the eye
- Ddemonstrated the protective function of the soluble form of FasL, thereby identifying a potentially useful therapeutic strategy
Using a gene therapy approach, Dr. Gregory-Ksander demonstrated that a single intravitreal injection of AAV2.sFasL provided complete and sustained neuroprotection in both the chronic DBA/2J and acute microbead-induced models of elevated IOP.
Dr. Gregory-Ksander’s lab is currently testing the effectiveness of the AAV2.sFasL gene therapy in protecting retinal ganglion cells in larger animal models of glaucoma. They are also using a combination of bone-marrow chimeras and tissue-specific Fas and FasL knock-out mice to determine the function of Fas/FasL signaling in the amplification of inflammation that occurs in the ONH and neural retina following elevated IOP and elucidate the mechanism by which sFasL provides such complete and sustained protection of the retinal ganglion cell body and axons of the optic nerve, even in the presence of sustained elevated IOP.
NLRP3 as a target for neuroprotection in Glaucoma
Dr. Gregory-Ksander recently made the discovery that NLRP3 was constitutively expressed in the optic nerve head of normal human and mouse eyes. Using the microbead-induced mouse model of elevated IOP, Dr. Gregory-Ksander demonstrated the requirement of inflammasome activation in axonal damage and death of retinal ganglion cells. The use of the microbead mouse model of elevated IOP in conjunction with inflammasome deficient mice and NLRP3 inhibitors, Dr. Gregory-Ksander has demonstrated the essential role that NLRP3 inflammasome activation plays in the development of inflammation in the optic nerve head (ONH), resulting in axonal damage and death of RGCs.
The current goal of this project is to:
- Understand how and why the NLRP3 inflammasome pathway becomes dysregulated in the development of glaucoma
- Develop and test novel inhibitors of the NLRP3 inflammasome pathway as a potential neuroprotective therapy in glaucoma
Fas Ligand and Vascular Leakage in Age-Related Macular Degeneration
Age-related macular degeneration (AMD) is the primary cause of blindness in patients 60 years of age and older. The growth of abnormal blood vessels into the retina is the main cause of severe vision loss, in part due to vessel leakage of blood and fluid that causes damage to the surrounding retinal tissue.
In collaboration with Dr. Ann Marshak-Rothstein at University Massachusetts School of Medicine in Worcester, Dr. Gregory-Ksander has identified a novel function for membrane Fas ligand in preventing vascular leakage. The goal of this study is to:
- Determine whether the administration of this protein can be used to prevent vascular leakage in a mouse model of laser-induced choroidal neovascularization
- Elucidate the mechanism of this protein