Michael G Anderson

University of Iowa | UI · Department of Molecular Physiology and Biophysics

Purpose: Exfoliation syndrome (XFS) is a systemic disease of elastin-rich tissues involving a deposition of fibrillar exfoliative material (XFM) in the anterior chamber of the eye, which can promote glaucoma. The purpose of this study was to create mice with CRISPR/Cas9-induced variations in candidate genes identified from human genome-wide associ...

Atomic force microscopy (AFM) is a valuable tool for assessing mechanical properties of biological samples, but interpretations of measurements on whole tissues can be difficult due to the tissue's highly heterogeneous nature. To overcome such difficulties and obtain more robust estimates of tissue mechanical properties, we describe an AFM force ma...

Evaluating optic nerve cross-sectional images requires significant time and effort by experts to perform. Autonomous systems using deep learning can help to reduce this workload by performing the evaluation automatically, though they tend to require labeled images to train, which can be time and effort intensive to produce. This work utilizes a sem...

Anterior chamber depth (ACD) is a quantitative trait associated with primary angle closure glaucoma (PACG). Although ACD is highly heritable, known genetic variations explain a small fraction of the phenotypic variability. The purpose of this study was to identify additional ACD-influencing loci using strains of mice. Cohorts of 86 N2 and 111 F2 mi...

PURPOSE Anterior chamber depth (ACD) is a quantitative trait associated with primary angle closure glaucoma (PACG). Although ACD is highly heritable, known genetic variations explain a small fraction of the phenotypic variability. The purpose of this study was to identify additional ACD-influencing loci using strains of mice. METHODS Cohorts of 86...

The Emory cataract (Em) mouse mutant has long been proposed as an animal model for age-related or senile cataract in humans - a leading cause of visual impairment. However, the genetic defect(s) underlying the autosomal dominant Em phenotype remains elusive. Here, we confirmed development of the cataract phenotype in commercially available Em/J mic...

Purpose: Assessment of glaucomatous damage in animal models is facilitated by rapid and accurate quantification of retinal ganglion cell (RGC) axonal loss and morphologic change. However, manual assessment is extremely time- and labor-intensive. Here, we developed AxoNet 2.0, an automated deep learning (DL) tool that (i) counts normal-appearing RG...

Purpose: Despite popularity of optical coherence tomography (OCT) in glaucoma studies, it's unclear how well OCT-derived metrics compare to traditional measures of retinal ganglion cell (RGC) abundance. Here, Diversity Outbred (J:DO) mice are used to directly compare ganglion cell complex (GCC) thickness measured by OCT to metrics of retinal anato...

Bardet–Biedl syndrome (BBS) is a rare ciliopathy for which there are no current effective treatments. BBS is a genetically heterogeneous disease, though the M390R mutation in BBS1 is involved in ~25% of all genetic diagnoses of BBS. The principle features of BBS include retinal degeneration, obesity, male infertility, polydactyly, intellectual disa...

Due to their similarities in anatomy, physiology, and pharmacology to humans, mice are a valuable model system to study the generation and mechanisms modulating conventional outflow resistance and thus intraocular pressure. In addition, mouse models are critical for understanding the complex nature of conventional outflow homeostasis and dysfunctio...

Mutations in CEP290 cause up to 30% of cases of Leber congenital amaurosis (LCA), a severe childhood blindness resulting from abnormalities in the photoreceptor connecting cilia that lead to rapid retinal degeneration. Like many genetic diseases, CEP290-LCA has considerable variable expressivity, indicating the presence of other factors that influe...

Purpose: Ocular tissues of mice have been studied in many ways using replication-deficient species C type 5 adenovirus (Ad5) as a tool for manipulating gene expression. Whereas refinements to injection protocols and tropism have led to several advances in targeting cells of interest, there remains a relative lack of information concerning how Ad5...

Purpose: Optic nerve damage is the principal feature of glaucoma and contributes to vision loss in many diseases. In animal models, nerve health has traditionally been assessed by human experts that grade damage qualitatively or manually quantify axons from sampling limited areas from histologic cross sections of nerve. Both approaches are prone t...

Central corneal thickness is a quantitative trait with important associations to human health. In a phenotype-driven approach studying corneal thickness of congenic derivatives of C57BLKS/J and SJL/J mice, the critical region for a quantitative trait locus influencing corneal thickness, Cctq1a , was delimited to a 10-gene interval. Exome sequencing...

The nee mouse model exhibits characteristic features of congenital glaucoma, a common cause of childhood blindness. The current study of nee mice had two components. First, the time course of neurodegeneration in nee retinal flat-mounts was studied over time using a retinal ganglion cell (RGC)-marker, BRN3A; a pan-nuclear marker, TO-PRO-3; and H&E...

Objectives – Endothelial cells that line the entire vascular system play a pivotal role in the control of various physiological processes including metabolism. Moreover, endothelial dysfunction is associated with many pathological conditions including obesity. Here, we assessed the role of the BBSome, a protein complex composed of eight Bardet-Bied...

Background Glaucoma is a leading cause of visual disability and blindness. Release of iris pigment within the eye, pigment dispersion syndrome (PDS), can lead to one type of glaucoma known as pigmentary glaucoma. PDS has a genetic component, however, the genes involved with this condition are largely unknown. We sought to discover genes that cause...

Purpose: The purpose of this study was to examine the influence of genetic background on the retinal ganglion cell (RGC) response to blast-mediated traumatic brain injury (TBI) in Jackson Diversity Outbred (J:DO), C57BL/6J and BALB/cByJ mice. Methods: Mice were subject to one blast injury of 137 kPa. RGC structure was analyzed by optical coheren...

Traumatic brain injuries (TBI) of varied types are common across all populations and can cause visual problems. For military personnel in combat settings, injuries from blast exposures (bTBI) are prevalent and arise from a myriad of different situations. To model these diverse conditions, we are one of several groups modeling bTBI using mice in var...

Purpose: Optic nerve damage is the principal feature of glaucoma and contributes to vision loss in many diseases. In animal models, nerve health has traditionally been assessed by human experts that grade damage qualitatively or manually quantify axons from sampling limited areas from histologic cross sections of nerve. Both approaches are prone to...

The nee mouse model exhibits characteristic features of congenital glaucoma, a common cause of childhood blindness. The current study of nee mice had two components. First, the time course of neurodegeneration in nee retinal flat-mounts was studied over time using a retinal ganglion cell (RGC)-marker, BRN3A; a pan-nuclear marker, TO-PRO-3; and H&E...

Purpose: Ocular tissues of mice have been studied in many ways using replication deficient species C type 5 adenoviruses (Ad5) as tools for manipulating gene expression. While refinements to injection protocols and tropism have led to several advances in targeting cells of interest, there remains a relative lack of information concerning how Ad5 ma...

Purpose Despite popularity of optical coherence tomography (OCT) in glaucoma studies, it’s unclear how well OCT-derived metrics compare to traditional measures of retinal ganglion cell (RGC) abundance. Here, Diversity Outbred (J:DO) mice are used to directly compare ganglion cell complex (GCC)-thickness measured by OCT to metrics of retinal anatomy...

In addition to needing acute emergency management, blast-mediated traumatic brain injury (TBI) is also a chronic disorder with delayed-onset symptoms that manifest and progress over time. While the immediate consequences of acute blast injuries are readily apparent, chronic sequelae are harder to recognize. Indeed, the identification of individuals...

The purpose of this study was to characterize acute changes in inflammatory pathways in the mouse eye following a blast-mediated TBI (bTBI) model, and to determine if modulation of these pathways could protect the structure and function of retinal ganglion cells (RGC). bTBI was induced in C57BL/6J male mice by exposure to three 20 PSI blast waves d...

Purpose: The purpose of this study was to examine the effect of multiple blast exposures and blast preconditioning on the structure and function of retinal ganglion cells (RGCs), to identify molecular pathways that contribute to RGC loss, and to evaluate the role of kynurenine-3-monooxygenase (KMO) inhibition on RGC structure and function. Method...

Purpose: Traumatic brain injury (TBI) is a risk factor for developing chronic neurodegenerative conditions including Alzheimer's disease (AD). The purpose of this study was to examine chronic effects of blast TBI on retinal ganglion cells (RGC), optic nerve, and brain amyloid load in a mouse model of AD amyloidosis. Methods: Transgenic (TG) doub...

The purpose of this study was to characterize acute changes in inflammatory pathways in the mouse eye following a blast-mediated TBI (bTBI) model, and to determine if modulation of these pathways could protect the structure and function of retinal ganglion cells (RGC). bTBI was induced in C57BL/6J male mice by exposure to three 20 PSI blast waves,...

Glaucoma is a neurodegenerative disease with elevated intraocular pressure as one of the major risk factors. Glaucoma leads to irreversible loss of vision and its progression involves optic nerve head cupping, axonal degeneration, retinal ganglion cell (RGC) loss, and visual field defects. Despite its high global prevalence, glaucoma still remains...

Purpose: The R345W mutation in EFEMP1 causes malattia leventinese, an autosomal dominant eye disease with pathogenesis similar to an early-onset age-related macular degeneration. In mice, Efemp1R345W does not cause detectable degeneration but small subretinal deposits do accumulate. The purpose of this study was to determine whether there were abn...

Chédiak-Higashi syndrome (CHS) is a lethal disorder caused by mutations in the LYST gene that involves progressive neurologic dysfunction. Lyst-mutant mice exhibit neurologic phenotypes that are sensitive to genetic background. On the DBA/2J-, but not on the C57BL/6J-background, Lyst-mutant mice exhibit overt tremor phenotypes associated with loss...

Neprilysin (NEP), an ectoenzyme that modulates inflammation by degrading neuropeptides, was recently identified in the human corneal epithelium. The cornea expresses many NEP substrates, but the function of NEP in homeostatic maintenance and wound healing of the cornea is unknown. We therefore investigated the role of this enzyme under naive and in...

Latanoprost is a common glaucoma medication. Here, we study longitudinal effects of sustained latanoprost treatment on intraocular pressure (IOP) in C57BL/6J mice, as well as two potential side-effects, changes in iris pigmentation and central corneal thickness (CCT). Male C57BL/6J mice were treated daily for 16 weeks with latanoprost. Control mice...

Objective: Mutations in myocilin (MYOC) may cause either juvenile open angle glaucoma (JOAG) or adult-onset primary open angle glaucoma (POAG). MYOC encodes a glycoprotein that is normally secreted from trabecular meshwork cells that regulate intraocular pressure. Prior in vitro, transgenic rodent, and organ culture experiments have suggested that...

Purpose: To compare the central corneal epithelial thickness (CET), stromal thickness (CST), and total thickness (CCT) in males with and without primary open-angle glaucoma and to determine the factors associated with corneal thickness. Methods: A case-control study was conducted to evaluate 116 male patients at the Miami Veterans Affair Medical...

Animal models are powerful tools for studying diseases that affect the eye, such as exfoliation syndrome (XFS). Two types of animal models have been used to investigate the pathophysiology of XFS and glaucoma. One class of models is engineered to have key features of a disease by alteration of their genome (genotype-driven animal models). LOXL1 is...

Purpose: To develop a sensitive scale of iris transillumination suitable for clinical and research use, with the capability of either quantitative analysis or visual matching of images. Methods: Iris transillumination photographic images were used from 70 study subjects with ocular or oculocutaneous albinism. Subjects represented a broad range o...

From early in the study of mammalian genetics, it was clear that modifiers can have a striking influence on phenotypes. Today, several modifiers have now been studied in enough detail to allow a glimpse of how they function and influence our perspective of disease. With respect to diseases of the eye, some modifiers are an important source of pheno...

Duplication of the TBK1 gene is associated with 1-2% of normal tension glaucoma, a common cause of vision loss and blindness that occurs without grossly abnormal intraocular pressure. We generated a transgenic mouse that has one copy of the human TBK1 gene (native promoter and gene structure) incorporated into the mouse genome (Tg-TBK1). Expression...

Scientific Reports 6 : Article number: 26559 10.1038/srep26559 ; published online: 26 May 2016 ; updated: 19 October 2016 In the Supplementary Information file originally published with this Article, Supplemental Figure 1 was omitted.

We have developed a publicly available tool, AxonJ, which quantifies the axons in optic nerve sections of rodents stained with paraphenylenediamine (PPD). In this study, we compare AxonJ’s performance to human experts on 100x and 40x images of optic nerve sections obtained from multiple strains of mice, including mice with defects relevant to glauc...

The inner surface of the retina contains a complex mixture of neurons, glia, and vasculature, including retinal ganglion cells (RGCs), the final output neurons of the retina and primary neurons that are damaged in several blinding diseases. The goal of the current work was two-fold: to assess the feasibility of using computer-assisted detection of...

Introduction: Several studies have indicated that autoimmune and neuroinflammatory processes contribute to the neurodegeneration of retinal ganglion cells in human glaucoma patients and in animal models. To test the involvement of cellular immune processes in the pathophysiology of retinal ganglion cell degeneration in vivo, we carried out adoptiv...

The present article introduces RetFM-J, a semi-automated ImageJ-based module that detects, counts, and collects quantitative data on nuclei of the inner retina from H&E-stained whole-mounted retinas. To illustrate performance, computer-derived outputs were analyzed in inbred C57BL/6J mice. Automated characterization yielded computer-derived outputs...

Central corneal thickness (CCT) is a quantitative trait associated with keratoconus and primary open-angle glaucoma. Although CCT is highly heritable, known genetic variations explain only a fraction of the phenotypic variability. The purpose of this study was to identify additional CCT-influencing loci using inbred strains of mice. Cohorts of 82 b...

We have observed that the commonly used ketamine/xylazine anesthesia mix can induce a focally severe and permanent corneal opacity. The purpose of this study was to establish the clinical and histological features of this deleterious side effect, its sensitivity with respect to age and anesthesia protocol, and approaches for avoiding it. Young C57B...

Purpose: TBI frequently leads to visual dysfunction. The purpose of this study was to investigate the effect of TBI on RGCs, and to test whether treatment with the novel neuroprotective compound P7C3-S243 could prevent functional deficits in the visual system. Methods: Blast-mediated TBI was induced in a blast chamber. RGC physiology was evaluated...

At present, no animal models fully embody exfoliation syndrome or exfoliation glaucoma. Both genetic and environmental factors appear critical for disease manifestation, and both must be considered when generating animal models. Because mice provide a powerful mammalian platform for modeling complex disease, this paper focuses on mouse models of ex...

Melanin within melanosomes exists as eumelanin or pheomelanin. Distributions of these melanins have been studied extensively within tissues, but less often within individual melanosomes. Here, we apply X-ray fluorescence analysis with synchrotron radiation to survey the nanoscale distribution of metals within purified melanosomes of mice. The study...

Melanosomes are highly specialized organelles that produce and store the pigment melanin, thereby fulfilling essential functions within their host organism. Besides having obvious cosmetic consequences - determining the color of skin, hair and the iris - they contribute to photochemical protection from ultraviolet radiation, as well as to vision (b...

Anterior segment optical coherence tomography (AS-OCT) is a non-invasive imaging modality that allows for the quantitative assessment of corneal thicknesses. Automated approaches for these measurements are not readily available and therefore measurements are often obtained manually. While graph-based approaches that enable the optimal simultaneous...

Objectives: To determine which metrics of scholarly output have the most impact on decisions for faculty promotion, as new forms of scholarship are evolving at medical schools to answer an emerging need for increased skills specialization and interdisciplinary collaboration. Methods: University of Iowa Carver College of Medicine (UICCOM) data was u...

A r t i c l e s Human ocular biometric parameters comprise a set of highly herit-able and often correlated quantitative traits. One notable example is CCT, which has an estimated heritability of up to 95% (ref. 1). Whereas extreme corneal thinning is a dramatic clinical feature for rare congenital connective tissue disorders, including brittle corn...

Central corneal thickness (CCT) is associated with eye conditions including keratoconus and glaucoma. We performed a meta-analysis on >20,000 individuals in European and Asian populations that identified 16 new loci associated with CCT at genome-wide significance (P < 5 × 10(-8)). We further showed that 2 CCT-associated loci, FOXO1 and FNDC3B, conf...

Purpose: We identified a pattern of concentric circular transillumination defects (TIDs) in a few patients with exfoliation syndrome (XFS) using an infrared detection system. This pattern of iris abnormality has also been observed in a mouse model of XFS. The objective of the current study is to determine whether concentric iris TIDs are specific...

Analysis of mutant mouse strains and linkage analysis with human families have both demonstrated that mutations influencing the podosomal adaptor protein SH3 and PX domains 2B (SH3PXD2B) can result in a congenital form of glaucoma. Here, we use immunohistochemistry to describe localization of the SH3PXD2B protein throughout the adult human eye and...

Glaucoma is a common ocular disorder that is a leading cause of blindness worldwide. It is characterized by the dysfunction and loss of retinal ganglion cells (RGCs). Although many studies have implicated various molecules in glaucoma, no mechanism has been shown to be responsible for the earliest detectable damage to RGCs and their axons in the op...

Mutations in the myocilin gene (MYOC) are the most common known genetic cause of primary open-angle glaucoma (POAG). The purpose of this study was to determine whether topical ocular sodium 4-phenylbutyrate (PBA) treatment rescues glaucoma phenotypes in a mouse model of myocilin-associated glaucoma (Tg-MYOC(Y437H) mice). Tg-MYOC(Y437H) mice were tr...

Mutations in myocilin (MYOC) are the most common genetic cause of primary open angle glaucoma (POAG), but the mechanisms underlying MYOC-associated glaucoma are not fully understood. Here, we report the development of a transgenic mouse model of POAG caused by the Y437H MYOC mutation; the mice are referred to herein as Tg-MYOC(Y437H) mice. Analysis...

Purpose: Mutations in SH3PXD2B cause Frank-Ter Haar syndrome, a rare condition characterized by congenital glaucoma, as well as craniofacial, skeletal, and cardiac anomalies. The nee strain of mice carries a spontaneously arising mutation in Sh3pxd2b. The purpose of this study was to test whether nee mice develop glaucoma. Methods: Eyes of nee m...

Glaucoma is a complex group of diseases causing progressive degeneration of the optic nerve. Despite strong evidence of hereditary contributions to glaucoma, relatively few genetic mutations associated with glaucoma risk have thus far been identified. Glaucoma likely represents a complex genetic trait influenced by multiple loci and many confoundin...

Experimental techniques allowing longitudinal studies of vascular disease progression or treatment effects are not readily available for most animal models. Thus, most existing studies are destined to either study individual time points or use large cohorts of animals. Here we describe a noninvasive technique for studying vascular disease that is b...

Several ocular diseases involve the iris, notably including oculocutaneous albinism, pigment dispersion syndrome, and exfoliation syndrome. To screen for candidate genes that may contribute to the pathogenesis of these diseases, genome-wide iris gene expression patterns were comparatively analyzed from mouse models of these conditions. Iris samples...

GPNMB is a unique melanosomal protein. Unlike many melanosomal proteins, GPNMB has not been associated with any forms of albinism, and it is unclear whether GPNMB has any direct influence on melanosomes. Here, melanosomes from congenic strains of C57BL/6J mice mutant for Gpnmb are compared to strain-matched controls using standard transmission elec...

The cornea is a specialized transparent tissue responsible for refracting light, serving as a protective barrier, and lending structural support to eye shape. Given its importance, the cornea exhibits a surprising amount of phenotypic variability in some traits, including central corneal thickness (CCT). More than a mere anatomic curiosity, differe...

Additional time points in the histologic analysis of B6.Tyrc-2J Lystbg-J irides. Histologic comparison of B6.Tyrc-2J (left column) and B6.Tyrc-2J Lystbg-J (right column) irides throughout postnatal development. (A–F) Throughout early postnatal development in day P4–P16 mice, B6.Tyrc-2J and B6.Tyrc-2J Lystbg-J eyes are histologically similar. Cells...

Additional time points in the histologic analysis of B6-Lystbg-J irides. Histologic comparison of C57BL/6J (left column) and B6-Lystbg-J (right column) irides throughout postnatal development. (A, B) At posnatal day 4 (P4), C57BL/6J and B6-Lystbg-J eyes are histologically similar. Cells of the iris stroma (thin arrows) are visibly distinguishable f...

Lyst mutation leads to increased levels of 4-HNE labeling and lipid hydroperoxide. 4-HNE labeling of C57BL/6J (left column) and B6-Lystbg-J (right column) eyes. Identical cryosections imaged with phase-contrast (top row) or epifluorescence (bottom row) microscopy. (A, C) C57BL/6J irides have modest 4-HNE labeling of the iris stroma (arrows). (B, D)...

D2.Lystbg-J mice exhibit no spinal cord or sciatic nerve degeneration. (A, B) Cross sections of the thoracic spinal cord stained with H&E. Images of the ventral grey matter illustrate similar numbers of motor neurons (arrows), indicating no nerve degeneration in D2.Lystbg-J compared to B6-Lystbg-J age-matched controls (n = 5 for each strain). (C, D...

Coat-color phenotypes of D2.Lystbg-J mice. Coat color of D2.Lystbg-J (left) and DBA/2J (right) mice. The Lystbg-J mutation causes a lightening of the DBA/2J coat color. (1.94 MB TIF)

Quantification of iris transillumination defects confirms that the DBA/2J-derived genetic enhancer of Lyst-mutant iris phenotypes maps to Tyrp1. Severity of transillumination defects quantified for multiple genotypes of mice. Transillumination defects were quantified based upon the amount of red light (R-value) in RGB formatted digital images of ir...

D2.Lystbg-J mice develop a severe tremor indicative of a neurodegenerative phenotype. Note that the D2.Lystbg-J mouse on the left (lighter coat color) has a severe tremor, whereas the B6-Lystbg-J mouse on the right (darker coat color) does not. (1.08 MB WMV)

Lyst and Tyrp1 are expressed in the mouse brain. RT-PCR analysis shows Lyst expression in the cerebral cortex, cerebellum, and brain stem (top panel), and Tyrp1 expression in the cerebellum and brain stem but not the cerebral cortex (bottom panel). (0.20 MB TIF)

LYST is a large cytosolic protein that influences the biogenesis of lysosome-related organelles, and mutation of the encoding gene, LYST, can cause Chediak-Higashi syndrome. Recently, Lyst-mutant mice were recognized to also exhibit an iris disease resembling exfoliation syndrome, a common cause of glaucoma in humans. Here, Lyst-mutant iris phenoty...

The STXMPy program suite. This file contains the sm and xanesP python libraries and various data processing scripts, described in this paper. A Readme.txt file is also included, describing the installation and some testing examples.

Example data set 1. STXM images of freeze dried melanosomes, recorded at the NSLS X1A beam line. Provided to test the program installation and functionality, presenting an example of uniform illumination in Figure 3a-c.

Example data set 2. Another STXM image set, this time with noisy data. Provided to demonstrate the line absorption algorithm. Further usage is described in the STXMPy.zip, in a Readme.txt file. This data presents intensity fluctuations, the source data of Figure 3d and Figure 4.

Soft X-ray spectromicroscopy based absorption near-edge structure analysis, is a spectroscopic technique useful for investigating sample composition at a nanoscale of resolution. While the technique holds great promise for analysis of biological samples, current methodologies are challenged by a lack of automatic analysis software e. g. for selecti...

Assessment of morphological vascular responses to exposure to cardiovascular risk factors in experimental animals requires ex vivo experiments that do not allow assessment of the time course of vascular alterations in individual subjects. We used a slit‐lamp biomicroscope (resolution <1 μm) to photograph the long posterior ciliary artery (LPCA) of...

Ocular involvement in muscular dystrophy ranges from structural defects to abnormal electroretinograms. While the mechanisms underlying the abnormal retinal physiology in patients are not understood, it is thought that alpha-dystroglycan extracellular interactions are critical for normal visual function. Here we show that beta-dystroglycan anchors...