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Former Research Scientist/Postdoctoral Fellows


Gareth Howell, Ph.D. 

Assistant Research Professor

Jackson Laboratory, Bar Harbor, Maine


Bio from time in John Lab
I received a Bachelor's degree in Molecular Biology from the University of Manchester, UK.  I went on to join The Wellcome Trust Sanger Institute, Cambridge, UK where I studied for my Ph.D. in comparative genomics and bioinformatics.  In 2003 I joined the laboratory of Dr. John Schimenti, at The Jackson Laboratory, as a Postdoctoral Fellow, gaining hands-on experience using mice to study genes contributing to developmental disease.  I returned to the UK, to train with Dr. Stuart Wilson and Dr. Marysia Plazcek at The University of Sheffield, in powerful new methods for gene-silencing.  

I returned to The Jackson Laboratory as an Associate Research Scientist in October 2005, working closely with Simon John to understand the neurobiology of glaucoma and to develop clinically relevant neuroprotective treatments. Under the strong mentorship of Simon, I received my first independent grant in 2006 and was subsequently promoted to Research Scientist.  

During my time with Simon, I have applied my bioinformatics and other experience in a number of different areas including identifying early stages of glaucomatous neurodegeneration.  A second major focus is the refinement of a radiation-based neuroprotective treatment that completely prevents optic nerve damage in DBA/2J mice. More recently, because of my strong genomics background, I am leading a major initiative to identify glaucoma-relevant genes in humans. We are using cutting edge sequencing technology to identify potential disease-causing variants in human glaucoma patients.

My time with Simon has been invaluable as a final training ground before beginning my independent career. My program covers both glaucoma and Alzheimer’s Disease (AD). For glaucoma, I am continuing to conduct experiments to understand the role of both the complement and endothelin systems. For AD, it has become clear to me that we can harness the power of mouse genetics and genomics to contribute a great deal to the understanding of this debilitating disease. 


Kayrat Saidas (Sai) Nair, Ph.D. Sai Nair  Ph.D
Assistant Professor
Department of Ophthalmology
UCSF, School of Medicine


Bio from time in John Lab

I received my Ph.D. in Biochemistry from the University of Mumbai, India. From there I became a Postdoctoral Fellow in the laboratory of Dr. Vladlen Slepak at the University of Miami.  My research focused on factors regulating phototransduction. With the advent of human/mouse genome sequencing, and emphasis shifting towards translational research, I felt it both timely and important to shift my research to examining ways to solve complex problems related to human diseases. With a background and interest in vision research, it was only appropriate to study ocular diseases. I joined the John Laboratory as a Postdoctoral Fellow in 2005. I have since progressed to a Research Scientist position, which allows me more independence, as well as the training and experience needed in preparation to become a PI. The goals of my projects are to understand genetic factors controlling intraocular pressure (IOP) elevation and glaucoma.

One of my projects focuses on understanding the genetic complexity underlying elevated IOP and glaucoma, using the DBA/2J mouse as a model. Using the power of mouse genetics, our goal is to identify genetic mutations and their interactions that confer susceptibility towards glaucoma. It is challenging to identify contributing casual genes in complex, late-age onset diseases.  We have been able to achieve this utilizing a specific gene mapping strategy that has been refined and well-proven in the John Lab.   Our mapping efforts have led to identification of 7 genetic loci that contribute to IOP elevation in this system. These loci interact with one another and modulate IOP elevation. Of these 7 loci, we have already identified three causal mutations. Understanding how these mutations and loci influence pathogenesis will help us identify pathways that govern susceptibility to glaucoma. Potentially, this could lead to new avenues to treat the disease in humans.  Additionally, this work has allowed us to gain insight into factors determining disease severity and penetrance. Success in this work is possible, because of the great expertise in ocular disease and in mechanistically dissecting complex diseases using mouse genetics in the John Lab. The great support provided by John Lab members and the general  Jackson Laboratory environment are also important.

Another project involves characterizing a much needed animal model that recapitulates features of angle closure glaucoma. Angle closure glaucoma (ACG) is a subset of glaucoma affecting 16 million people. ACG is estimated to blind more people worldwide than other common forms of glaucoma, with 4 million people being bilaterally blind. The genetic and molecular mechanisms of IOP elevation in ACG are not understood but a reduced ocular size is common.  A chemical mutagenesis screen led to identification of a mutant mouse strain with reduced ocular size and a phenotype resembling ACG. Subsequently, we have identified the gene responsible for this condition. Comparative genetics has led to identification of mutations in the same gene in human families with similar phenotypes.


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.
Associate Professor of Physiology & Biology

University of Iowa


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.




Richard Libby, Ph.D.
Assistant Professor

Department of Ophthalmology
University of Rochester Eye Institute


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.
Professor/Investigator
Center for Human Molecular Biology & Genetics , Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital Chengdue, Sichuan, China
      

Dr. Zhu received his B.Sc. degree in Plant Molecular and Developmental Biology from Peking University, Beijing. He went on to study in the Institute of Microbiology, at the Chinese Academy of Sciences, Beijing and received his master degree in Biochemistry and Molecular Biology.  In 2000, Dr. Zhu entered the program of Cell and Molecular Biology of the University of Texas, Austin and worked in Dr. David Stein's lab for his Ph.D. dissertation. A major component of the project was to determine the molecular mechanism that controls Drosophila dorsal-ventral polarity formation, specifically investigating the role of glycosaminoglycans in Drosophila pipe-mediated dorsal-ventral patterning. 

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.  Dr.  Zhu also investigated the possible role of glial cells in the initiation and/or propagation of glaucoma.  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





Ileana Soto, Ph.D.
Associate Research Scientist
Jackson Laboratory, Bar Harbor, Maine
                                                   
Bio from time in J
ohn Lab
I graduated with a B.A. in Life Sciences from the University of Puerto Rico. As an undergraduate student I worked in the laboratory of Dr. Rosa Blanco at the Institute of Neurobiology.  The research experience was so great that I decided to apply for graduate school and continue doing research in her laboratory.  My thesis project in Dr. Blanco’s laboratory consisted of determining the effects of basic fibroblast growth factor (bFGF) in the survival and axonal regeneration of frog retinal ganglion cells (RGCs) after optic nerve axotomy. In 2005, I received my Ph.D. from the Biology Intercampus Program at University of Puerto Rico. My studies in the frog visual system encouraged me to continue further studies of the retina but with a more biomedical perspective.  

During my first postdoctoral training experience at Johns Hopkins University, I had the opportunity to work in the DBA/2J mouse glaucoma model and to study molecular changes that occur in RGCs and glial cells during the progression of  glaucoma.  However, a deeper interest for the role of astrocytes in glaucoma, and the use of mouse genetics to identify pathways and experimentally test mechanisms motivated me to join Dr. Simon John’s laboratory for a second postdoctoral training.  My major projects are assessing the interactions between glaucoma and diabetes and the impact of dietary components on disease outcome.  I plan to address whether cellular pathways activated in astrocytes contribute positively or negatively to disease onset and progression.  I am also interested in possible therapeutic treatments that prevent or delay the progression of the disease in mouse glaucoma models. My goal is to identify certain mechanisms involved in the pathophysiology of glaucoma that can then be targeted for the treatment of the human disease.

           




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