We study glaucoma as well as other eye and neural diseases. Glaucoma is possibly the most common neurodegenerative disease affecting about 80 million people. Glaucoma leads to the death of retinal ganglion cells, the cells that connect the eye to the brain. Glaucoma is often associated with harmfully elevated pressure within the eye itself, called intraocular pressure (IOP). This harmful pressure damages retinal ganglion cells (RGCs) resulting in a pressure-induced neurodegeneration. The molecular processes that raise IOP and damage retinal ganglion cells are only partially understood.
We study the genetics, genomics and neurobiology of glaucoma using powerful mouse models to understand molecular mechanisms. We are identifying genes, pathways and aberrant processes that lead to high IOP and glaucoma. We are determining how high IOP damages retinal neurons as well developing resilience-boosting and neuroprotective treatments to shield RGCs from glaucoma. Resilience-boosting treatments beneficially adjust cellular metabolism and/or increase other cellular resources that protect from stress, enhancing the ability of ocular tissues to fend off disease.
We demonstrated that vitamin B3 (nicotinamide) potently prevents glaucoma in a mouse model. We have a growing interest in the role of altered metabolism in IOP elevation and retinal disease. We are involved with clinical trials and other studies to further evaluate the efficacy of vitamin B3 and the role of metabolism in human glaucoma.
Interests include: 1) the neuroimmunology of glaucoma and the roles of specific immune cells and molecules 2) the neural control of intraocular pressure with the characterization of participating neuronal cell types 3) molecular characterization of various cell types during glaucoma using single cell sequencing and other approaches, including testing the roles of specific molecules in RGC axonal and somal degeneration, 4) characterizing metabolic changes impacting glaucoma and 5) developing various nutritional and gene-therapy based interventions.
- Glaucoma , ocular and neural diseases
- Metabolic abnormalities and disease susceptibility
- Genetic and genomic control of disease
- Retinal ganglion cells and neurodegeneration
- Compartmentalized degeneration pathways (e.g. somal and axonal intrinsic pathways)
- Neuroimmunology and disease
- Gene-therapy and resilience boosting treatments
Harder JM, Guymer C, Wood JPM, Daskalaki E, Chidlow G, Zhang C, Balasubramanian R, Cardozo BH, Foxworth NE, Deering KE, Ouellette TB, Montgomery C, Wheelock CE, Casson RJ, Williams PA, John SWM. 2020. Disturbed glucose and pyruvate metabolism in glaucoma with neuroprotection by pyruvate or rapamycin. Proc Natl Acad Sci U S A 117(52):33619-33627
Williams PA, Harder JM, Foxworth NE, Cochran KE, Philip VM, Porciatti V, Smithies O, John SWM. 2017. Vitamin B3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice. Science 355(6326):756-760
Harder JM, Braine CE, Williams PA, Zhu X, MacNicoll KH, Sousa GL, Bucahanan RA, Smith RS, Libby RT, Howell GR, John SWM. 2017. Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective. Proc Natl Acad Sci U S A 114(19):E3839-E3848
Howell GR, MacNicoll KH, Braine CE, Soto I, Macalinao DG, Sousa GL, John SWM. 2014. Combinatorial targeting of early pathways profoundly inhibits neurodegeneration in a mouse model of glaucoma. Neurobiol Dis 11 (71):44-52
Kizhatil K, Ryan M, Marchant J, Henrich S, John SWM. 2014. Schlemm’s canal is a unique vessel with a combination of blood vascular and lymphatic phenotypes that forms by a novel developmental process. PloS Biol 12(7):e1001912
*Howell GR, Soto I, Zhu X, Ryan M, Macalinao DG, Sousa GL, Caddle LB, MacNicoll KH, Barbay JM, Porciatti V, Anderson MG, Smith RS, Clark AF, Libby RT, John SWM. 2012. Radiation treatment inhibits monocyte entry into the optic nerve head and prevents neuronal damage in a mouse model of glaucoma. J Clin Invest 122(4):1246-61. *Lewis Rudin Glaucoma Prize for outstanding glaucoma paper in 2012
Nair KS, Hmani-Aifa M, Ali Z, Kearney A, Salem SB, Macalinao DG, Cosma IM, Bouassida W, Hakim B, Benzina Z, Soto I, Söderkvist P, Howell GR, Smith RS, Ayadi H, John SWM. 2011. Alteration of the serine protease PRSS56 causes angle-closure glaucoma in mice and posterior microphthalamia in humans and mice. Nat Genet 43(6):579-584
*Lachke SA, Alkuraya FS, Kneeland SC, Ohn T, Aboukhalil A, Howell GR, Saadi I, Cavallesco R, Yue Y, Tsai ACH, Nair KS, Cosma MI, Smith RS, Hodges E, AlFadhli SM, Al-Hajeri A, Shamseldin HE, Behbehani AM, Hannon GJ, Bulyk ML, Drack AV, Anderson PJ, John SWM**, Maas RL**. 2011. Mutations in the RNA Granule Component TDRD7 Cause Cataract and Glaucoma. Science 331:1571-1576. **Joint corresponding authors *Highlighted paper, Faculty of 1000 Biology http://f1000.com/9919957
Howell GR, Macalinao DG, Sousa GL, Walden M, Soto I, Kneeland SC, Barbay JM, King BL, Marchant JK, Hibbs M, Stevens B, Barres BA, Clark AF, Libby RT, John SWM. 2011. Molecular clustering identified complement and endothelin induction as early events in a mouse glaucoma. J Clin Invest 121:1429-1444
Howell GR, Libby RT, Jakobs TC, Smith RS, Phalan FC, Barter JW, Barbay JM, Marchant JK, Mahesh N, Porciatti V, Whitmore AV, Masland RH, John SWM. 2007. Axons of retinal ganglion cells are insulted in the optic nerve early in DBA/2J glaucoma. J Cell Biol 179:1523-1537
*Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, Germaine Bousser M, Heutink P, Miner JH, Tournier-Lasserve E, John SWM. 2006. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. N E J Med 354:1489-1496 *Highlighted paper, Faculty of 1000 Biology http://f1000.com/12625
Libby RT, Yan L, Savinova OV, Barter J, Smith RS, Nickells RW, John SWM. 2005. Susceptibility to neurodegeneration in a glaucoma is modified by Bax gene dosage. PLoS Genet 1:17-26
*Gould DB, Phalan FC, Breedveld GJ, van Mil SE, Smith RS, Schimenti JC, Aguglia U, van der Knaap MS, Heutink P, John SWM. 2005. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. Science 308:1167-1171 *Highlighted paper, Faculty of 1000 Biology http://www.f1000biology.com/article/id/1026611/evaluation
*Anderson MG, Libby RT, Gould DB, Smith RS, John SWM. 2005. High-dose radiation with bone marrow transfer prevents neurodegeneration in an inherited glaucoma. Proc Natl Acad Sci USA 102:4566-4571. * World-wide glaucoma award for daring, breakthrough, creative, original body of work & for most important paper in glaucoma in 2005.
Mo JS, Anderson MG, Gregory M, Smith RS, Savinova OV, Serreze DV, Ksander BR, Streilein JW, John SWM. 2003. By altering ocular immune privilege, bone marrow-derived cells pathogenically contribute to DBA/2J pigmentary glaucoma. J Exp Med 197: 1335-1344
*Libby RT, Smith RS, Savinova OV, Zabaleta A, Martin JE, Gonzalez FJ, John SWM. 2003. Modification of ocular defects in mouse developmental glaucoma models by tyrosinase. Science 299:1578-1581 *Lewis Rudin Glaucoma Prize, for most significant glaucoma paper in 2003
Anderson MG, Smith RS, Hawes NL, Zabaleta A, Chang B, Wiggs JL, John SWM. 2002. Mutations in genes encoding melanosomal proteins cause pigmentary glaucoma in DBA/2J mice. Nat Genet 30:81-85