Doug Gould, Ph.D.
Assistant Professor of Ophthalmology and Anatomy University of California San Francisco Institute of Human Genetics  Dr. Gould obtained his B.Sc. with Specialization in Genetics and his Ph.D. in Medical Genetics from the University of Alberta in Edmonton, Canada. His Ph.D. thesis, in the lab of Dr. Michael Walter, was to understand the molecular mechanisms that underlie ocular developmental defects. These defects often lead to glaucoma in human families. In 2001, Dr. Gould moved to Dr. John’s Lab to undergo postdoctoral training. Doug’s projects were primarily focused
on using mouse models to understand the mechanisms of glaucoma. In the
first of his two main projects, Doug sought to understand how mutations
in the myocilin gene (Myoc) lead to primary open angle glaucoma (POAG).
MYOC mutations are the most frequently identified genetic cause of POAG,
but the pathogenic mechanism(s) remained elusive. Doug tested two
contemporary hypotheses about MYOC pathogenesis by first characterizing a
mouse model that over-expressed the MYOC protein and secondly by
characterizing a mouse model that expressed a mutant Myoc allele that
was analogous to a common and aggressive human mutation. Doug’s data
indicate that abnormal protein molecules are necessary to induce disease
and show that accumulation of these molecules in ocular cells is not
sufficient to induce glaucoma. These data agree with a growing
literature from other groups and a recent report suggesting that the
abnormal mutant proteins have to be mis-targeted to the peroxisome to
cause glaucoma. Doug’s second major project was to
develop new mouse models of glaucoma. A novel mutant mouse line was
identified in a mutagenesis screen. Doug mapped the gene and identified a
mutation in the type IV collagen alpha 1 gene (Col4a1). He showed that
Col4a1 mutation can cause ocular dysgenesis in a genetic context
dependent manner. On a permissive background mutant mice have severe
anterior segment dysgenesis and optic nerve hypoplasia. On a resistant
background both phenotypes are profoundly modified and we have
identified a genetic modifier locus that is able to rescue anterior
segment dysgenesis. While identifying the gene and
characterizing the ocular phenotypes, the John Lab discovered that Col4a1 mutant
mice also had cerebrovascular defects including large cerebral cavities
and multi-focal cerebral hemorrhages. This work led to the
identification of COL4A1 mutations as a major genetic cause of a rare
but severe human disease called porencephaly and the speculation that
alleles of COL4A1 may contribute more broadly to hemorrhagic stroke in
human patients. Importantly, Doug’s experiments show that Col4a1
mutations weaken blood vessels and predispose to trauma-induced
hemorrhage in mice. Important collaborations demonstrated that this is
also true in some human families. This work suggests that behavioral
modifications/interventions may substantially decrease the risk of
severe (even lethal) hemorrhage that can be induced by trauma in
individuals with these mutations at all stages of life. Dr. Gould started his own laboratory in
2006 at UCSF School of Medicine in the Departments of Ophthalmology and
Anatomy and the Institute for Human Genetics where he is continuing to
study the mechanisms of Col4a1-related pathogenesis in the eye and other
organs. He rapidly obtained external funding, including NIH, and has been honored by awards. His email is gouldd@vision.ucsf.edu.
Michael Anderson, Ph.D.  Dr. Anderson performed his graduate work studying developmental neurobiology utilizing Drosophila. During his postdoctoral studies with Dr. John his research focused on the mechanisms causing glaucoma in DBA/2J mice. These mice develop a pigment liberating iris disease and a form of glaucoma resembling human pigmentary glaucoma. Using genetic approaches, two genes were identified (Gpnmb and Tyrp1) that play early roles in this disease. Both of these genes encode melanosomal proteins. These findings suggested that a key
aspect of pigmentary glaucoma in DBA/2J mice involves aberrant
melanosomal processes affecting the toxic intermediates of melanin
production. In the course of studying modifiers of the DBA/2J form of
glaucoma, Dr. Anderson's research also found that immune reactions
contribute to the anterior chamber disease of DBA/2J mice and with other
lab members showed that bone marrow transfers confer a striking
neuroprotection against this form of glaucoma. Dr. Anderson is currently a member of the Departments of Molecular Physiology & Biophysics and Ophthalmology & Visual Sciences at the University of Iowa. His ongoing work continues to capitalize on the basic genetic skills of his past training, utilizing mouse genetics to provide and test unique hypotheses of ocular disease and now supplemented by clinical and human genetic resources at The University of Iowa. His program is well established with several NIH grants and he recently became tenured. His email is michael-g-anderson@uiowa.edu.
Rick Libby, Ph.D.  Dr. Libby did his doctoral work in Dr. William Brunken’s laboratory (Boston College), where he focused on the role of extracellular matrix in retinal development. After completion of his doctorate, he joined Dr. Karen Steel’s group at the Medical Research Council’s Institute for Hearing Research. There he studied the pathogenesis of Usher Syndrome. The majority of work that Dr. Libby
performed in the John Laboratory focused on the DBA/2J mouse glaucoma
model. The DBA/2J mouse glaucoma model mimics many human glaucomas in
that it is age-related and the pressure elevation is spontaneous and
variable. There is now extensive knowledge of the disease profile of
DBA/2J mice and the John Lab has been successfully exploiting this model to gain
fundamental insight into glaucomatous neurodegeneration. Dr. Libby's role was to identify the key molecules and pathways that are activated in response to elevated intraocular pressure, and which lead to vision loss. Furthermore, he was interested in identifying susceptibility factors underlying galucomatous neurodegeneration. Using DBA/2J mice deficient in the
pro-apoptotic molecule BAX (a molecule that when active, triggers a cell
to kill itself), he found that Bax deficiency completely protected
retinal ganglion cells (RGCs; the cell bodies or soma) from apoptosis.
BAX was the first molecule shown to be necessary for glaucomatous RGC
death. However, BAX was not found to be required for RGC axon
degeneration. (In addition to a cell body, RGCs have a long process
known as an axon that connects them to the brain.) This is important
because it is the first data indicating that there are distinct somal
and axonal degeneration pathways in glaucoma. Furthermore, since axons
degenerated even though the soma did not, these results indicate that
somal death is not a prerequisite for axon degeneration in glaucoma. While Bax deficiency did not protect RGC
axons from degeneration, it did delay axon degeneration, implicating
BAX as a potential glaucoma susceptibility gene. These data suggest that a patient’s
susceptibility to glaucomatous vision loss could be directly linked to
Bax expression levels and that manipulating the BAX pathway could be a
powerful mechanism for slowing or preventing vision loss in glaucoma. In
collaboration with Dr. Robert Nickell's (University of Wisconsin) group,
we were also able to use the genetic resource of DBA/2J mice deficient
in Bax to evaluate two prominent glaucoma hypotheses. Genetically
controlled experiments were performed where RGC cells were insulted by
either mechanical axon injury or by an excitotoxin. The findings from
these induced cell death models were compared to the findings obtained
in the actual DBA/2J glaucoma. As in the actual glaucoma, Bax deficiency
protected somas after optic nerve crush, but it did not protect RGC
somas from excitotoxic injury. Together, these results support optic
nerve injury as a primary cause of RGC death in glaucoma but do not
support an excitotoxic mechanism. During his time in the John Lab, Dr.
Libby also participated in other projects ranging from studies designed
to identify susceptibility factors for developing glaucoma (blood
pressure, problems with eye development) to studies focused on
developing neuroprotective therapies (radiation with bone marrow
transfer). Dr. Libby started his own research program at the University of Rochester Medical Center in 2006. He is Assistant Professor in the Department of Ophthalmology where he continues to study the molecular pathways of glaucomatous neurodegeneration and the genetic factors that underlie genetic susceptibility. He rapidly obtained external funding, including NIH, and serves on various grant review bodies. His email is richard_libby@urmc.rochester.edu
Xianjun Zhu, Ph.D.  Dr. Zhu received his Ph.D. degree in Cell and Molecular Biology in 2006. He then joined the John Lab to pursue his postdoctoral training using mammalian genetics and neurobiologic methods to study neurodegenerative disease. He gained expertise in experiments to test mechanisms of disease using mouse models of human disease, and in ocular, brain and spinal cord anatomy and pathology. His major project studied neurodegeneration in wabbler lethal (wl) mice. He determined that these mice develop a severe axonopathy affecting various nerves, the retina and parts of the brain. Interestingly, although their axons degenerate, the neuronal cell bodies survive in most affected tissues. Dr. Zhu characterized the mutant gene which affects cell membranes. This study is being prepared for publication. Dr. Zhu also investigated the possible role of glial cells in the initiation and/or propagation of glaucoma. These projects are also being prepared for publication. Dr. Zhu is currently a Professor/Investigator at The Center for Human Molecular Biology & Genetics, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital Chengdu, Sichuan, China
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