Gogce C Crynen

• Ph.D.
• Analyst at The Scripps Research Institute

Human proteins repurposed as biologics for clinical use have been engineered through in vitro techniques that improve the affinity of the biologics for their ligands. However, the techniques do not select against properties, such as protease sensitivity or self-reactivity, that impair the biologics’ clinical efficacy. Here we show that the B-cell r...

Rhes (Ras homolog enriched in the striatum), a multifunctional protein that regulates striatal functions associated with motor behaviors and neurological diseases, can shuttle from cell to cell via the formation of tunneling-like nanotubes (TNTs). However, the mechanisms by which Rhes mediates diverse functions remain unclear. Rhes is a small GTPas...

Mice adoptively transferred with mouse B cells edited via CRISPR to express human antibody variable chains could help evaluate candidate vaccines and develop better antibody therapies. However, current editing strategies disrupt the heavy-chain locus, resulting in inefficient somatic hypermutation without functional affinity maturation. Here we sho...

Huntington disease (HD) is caused by an expanded polyglutamine mutation in huntingtin (mHTT) that promotes prominent atrophy in the striatum and subsequent psychiatric, cognitive deficits, and choreiform movements. Multiple lines of evidence point to an association between HD and aberrant striatal mitochondrial functions; however, the present knowl...

Many human proteins have been repurposed as biologics for clinical use. These proteins have been engineered with in vitro techniques that improve affinity for their ligands. However, these approaches do not select against properties that impair efficacy such as protease sensitivity or self-reactivity. Here we engineer the B-cell receptor of primary...

Many human proteins have been repurposed as biologics for clinical use. These proteins have been engineered with in vitro techniques that improve affinity for their ligands. However, these approaches do not select against properties that impair efficacy such as protease sensitivity or self-reactivity. Here we engineer the B-cell receptor of primary...

CRISPR-edited murine B cells engineered to express human antibody variable chains proliferate, class switch, and secrete these antibodies in vaccinated mice. However, current strategies disrupt the heavy-chain locus, resulting in inefficient somatic hypermutation without functional affinity maturation. Here we show that recombined murine heavy- and...

Target occupancy is often insufficient to elicit biological activity, particularly for RNA, compounded by the longstanding challenges surrounding the molecular recognition of RNA structures by small molecules. Here we studied molecular recognition patterns between a natural-product-inspired small-molecule collection and three-dimensionally folded R...

RNA is challenging to target with bioactive small molecules, particularly those of low molecular weight that bind with sufficient affinity and specificity. In this report, we developed a platform to address this challenge, affording a novel bioactive interaction. An RNA-focused small-molecule fragment collection (n = 2500) was constructed by analyz...

Background Inflammatory bowel disease (IBD) involves chronic T cell–mediated inflammatory responses. Vedolizumab (VDZ), a monoclonal antibody against α4β7 integrin, inhibits lymphocyte extravasation into intestinal mucosae and is effective in ulcerative colitis (UC) and Crohn’s disease (CD). Aim We sought to identify immune cell phenotypic and gen...

Completion of the Lassa virus (LASV) life cycle critically depends on the activities of the virally encoded, RNA-dependent RNA polymerase in replication and transcription of the viral RNA genome in the cytoplasm of infected cells. The contribution of cellular proteins to these processes remains unclear. Here, we applied proximity proteomics to defi...

Ebola virus (EBOV) critically depends on the viral polymerase to replicate and transcribe the viral RNA genome in the cytoplasm of host cells, where cellular factors can antagonize or facilitate the virus life cycle. Here we leverage proximity proteomics and conduct a small interfering RNA (siRNA) screen to define the functional interactome of EBOV...

Cerebrovascular dysfunction is a hallmark feature of Alzheimer's disease (AD). One of the greatest risk factors for AD is the apolipoprotein E4 (E4) allele. The APOE4 genotype has been shown to negatively impact vascular amyloid clearance, however, its direct influence on the molecular integrity of the cerebrovasculature compared to other APOE vari...

Background: Tumor heterogeneity may lead to false negative test results for tissue biopsy-based companion diagnostic tests. Real-time polymerase chain reaction (PCR) and digital PCR assays are used to detect rare alleles in cell-free circulating DNA for liquid biopsies; however, those tests lack strong sensitivity at low allele frequencies. We sho...

Ebola virus (EBOV) critically depends on the viral polymerase to replicate and transcribe the viral RNA genome. To examine whether interactions between EBOV polymerase and cellular and viral factors affect distinct viral RNA synthesis events, we applied proximity proteomics to define the cellular interactome of EBOV polymerase, under conditions tha...

Completion of the Lassa virus (LASV) life cycle critically depends on the activities of the virally encoded RNA-dependent RNA polymerase in replication and transcription of the negative-sense RNA viral genome in the cytoplasm of infected cells. We hypothesized that interactions with an array of cellular proteins may enable LASV polymerase to execut...

Cerebrovascular dysfunction and cerebral amyloid angiopathy (CAA) are hallmark features of Alzheimer's disease (AD). Molecular damage to cerebrovessels in AD may result in alterations in vascular clearance mechanisms leading to amyloid deposition around blood vessels and diminished neurovascular-coupling. The sequelae of molecular events leading to...

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein mediates infection of cells expressing angiotensin-converting enzyme 2 (ACE2). ACE2 is also the viral receptor of SARS-CoV (SARS-CoV-1), a related coronavirus that emerged in 2002–2003. Horseshoe bats (genus Rhinolophus) are presumed to be the original reservoir of b...

Background Mutations in DYRK1A are a cause of microcephaly, autism spectrum disorder, and intellectual disability; however, the underlying cellular and molecular mechanisms are not well understood. Methods We generated a conditional mouse model using Emx1-cre, including conditional heterozygous and homozygous knockouts, to investigate the necessit...

CRISPR effector proteins introduce double-stranded breaks into the mammalian genome, facilitating gene editing by non-homologous end-joining or homology-directed repair. Unlike the more commonly studied Cas9, the CRISPR effector protein Cas12a/Cpf1 recognizes a T-rich protospacer adjacent motif (PAM) and can process its own crRNA array, simplifying...

The etiology of inflammatory bowel disease (IBD) is unknown. However, chronic inflammation from T cell activation and its subsequent tissue damage is implicated in the pathogenesis of IBD. Vedolizumab (VDZ), a monoclonal antibody against α4β7 integrin that prevents T cell homing to intestinal mucosae, has shown efficacy in treating both ulcerative...

A real-time dPCR system was developed to improve the sensitivity, specificity and quantification accuracy of end point dPCR. We compared three technologies – real-time qPCR, end point dPCR and real-time dPCR – in the context of SARS-CoV-2. Some improvement in limit of detection was obtained with end point dPCR compared with real-time qPCR, and the...

Vascular endothelial growth factor A (VEGFA) stimulates angiogenesis in human endothelial cells, and increasing its expression is a potential treatment for heart failure. Here, we report the design of a small molecule (TGP-377) that specifically and potently enhances VEGFA expression by the targeting of a non-coding microRNA that regulates its expr...

Background: The ventricular system plays a vital role in blood-cerebrospinal fluid (CSF) exchange and interstitial fluid-CSF drainage pathways. CSF is formed in the specialized secretory tissue called the choroid plexus, which consists of epithelial cells, fenestrated capillaries and the highly vascularized stroma. Very little is currently known a...

Hydrogen/Deuterium Exchange (HDX) coupled with Mass Spectrometry (HDX-MS) is a sensitive and robust method to probe protein conformational changes and protein-ligand interactions. HDX-MS relies on successful proteolytic digestion of target proteins under acidic conditions to localize perturbations in exchange behavior to protein structure. The abil...

Rhes (Ras homolog enriched in the striatum) is a multifunctional protein that orchestrates striatal toxicity, motor behaviors and abnormal movements associated with dopaminergic signaling, Huntington disease and Parkinson disease signaling in the striatum. Rhes engineers membranous tunneling nanotube-like structures and promotes intercellular prote...

The original version of this article unfortunately contained a mistake. Gary S. Laco should not be listed as an author in the author group.

The therapeutic effects of l -3,4-dihydroxyphenylalanine ( l -DOPA) in patients with Parkinson’s disease (PD) severely diminishes with the onset of abnormal involuntary movement, l -DOPA–induced dyskinesia (LID). However, the molecular mechanisms that promote LID remain unclear. Here, we demonstrated that RasGRP1 [(guanine nucleotide exchange facto...

No concerted investigation has been conducted to explore overlapping and distinct pathobiological mechanisms between repetitive mild traumatic brain injury (r-mTBI) and tau/amyloid proteinopathies considering the long history of association between TBI and Alzheimer’s disease. We address this problem by using unbiased proteomic approaches to genera...

Benefits and risks were reported for hormone therapy (HT) to prevent chronic disease, including Alzheimer’s disease (AD). While the Women’s Health Initiative (WHI) found no protective effect of HT on the cognitive function of women whose treatment was initiated far past the onset of menopause, other studies showed reduced risk of AD with midlife tr...

The therapeutic benefits of L3,4 dihydroxyphenylalanine (L-DOPA) in Parkinson disease (PD) patients diminishes with the onset of abnormal involuntary movements (L-DOPA induced dyskinesia), a debilitating motor side effect. L-DOPA induced dyskinesia are due to altered dopaminergic signaling in the striatum, a brain region that controls motor and cog...

p>Vascular Endothelial Growth Factor A (VEGFA) stimulates angiogenesis in human endothelial cells and increasing its expression is a potential treatment for heart failure, currently accomplished via gene or mRNA therapy. Herein, we describe a designed small molecule (TGP-377) that specifically and potently enhances VEGFA expression by targeting of...

Retinoic acid inducible gene-I (RIG-I) ensures immune surveillance of viral RNAs bearing a 5’-triphosphate (5’ppp) moiety. Mutations in RIG-I (C268F and E373A) lead to impaired ATPase activity, thereby driving hyperactive signaling associated with autoimmune diseases. Here we report, using hydrogen/deuterium exchange, mechanistic models for dysregu...

Validation of changes in plasma LRG expression levels using antibody based ELISA approach in repetitive mTBI mice at multiple time points post-injury. (A) Represents ratio of BCA corrected ELISA concentration values normalized to 24 h post-injury time point for repetitive mTBI only group. (B) Represents values from proteomic analyses using TMT labe...

Validation of changes in plasma complement factor I expression levels using antibody based ELISA approach in repetitive mTBI mice at multiple time points post-injury. (A) Represents ratio of BCA corrected ELISA concentration values normalized to 24 h post-injury time point for repetitive mTBI only group. (B) Represents values from proteomic analyse...

Validation of changes in plasma alpha-2-macroglobulin expression levels using antibody based ELISA approach in sham and repetitive mTBI mice at multiple time points post-injury. (A) Represents ratio of BCA corrected ELISA concentration values normalized to 24 h post-injury time point for sham and repetitive mTBI only group. (B) Represents values fr...

The relationship between repetitive mild traumatic brain injury (r-mTBI) and Alzheimer’s disease (AD) is well-recognized. However, the precise nature of how r-mTBI leads to or precipitates AD pathogenesis is currently not understood. Plasma biomarkers potentially provide non-invasive tools for detecting neurological changes in the brain, and can re...

Many RNAs cause disease; however, RNA is rarely exploited as a small-molecule drug target. Our programmatic focus is to define privileged RNA motif small-molecule interactions to enable the rational design of compounds that modulate RNA biology starting from only sequence. We completed a massive, library-versus-library screen that probed over 50 mi...

Tau pathology associated with chronic traumatic encephalopathy has been documented in the brains of individuals with a history of repetitive mild traumatic brain injury (r-mTBI). At this stage, the pathobiological role of tau in r-mTBI has not been extensively explored in appropriate preclinical models. Herein, we describe the acute and chronic beh...

The cerebral accumulation and cytotoxicity of amyloid beta (Aβ) is central to Alzheimer's pathogenesis. However, little is known about how the amyloid pathology affects the global expression of brain proteins at different disease stages. In order to identify genotype and time-dependent significant changes in protein expression, we employed quantita...

Traumatic brain injury (TBI) is a serious public health concern which strikes someone every 15 s on average in the US. Even mild TBI, which comprise as many as 75% of all TBI cases, carries long term consequences. The effects of age and sex on long term outcome from TBI is not fully understood, but due to the increased risk for neurodegenerative di...

Objective Exposure to repetitive concussion, or mild traumatic brain injury (mTBI), has been linked with increased risk of long‐term neurodegenerative changes, specifically chronic traumatic encephalopathy (CTE). To date, preclinical studies largely have focused on the immediate aftermath of mTBI, with no literature on the lifelong consequences of...

CD4+ T cells are tightly regulated by microbiota in the intestine, but whether intestinal T cells interface with host-derived metabolites is less clear. Here, we show that CD4+ T effector (Teff) cells upregulated the xenobiotic transporter, Mdr1, in the ileum to maintain homeostasis in the presence of bile acids. Whereas wild-type Teff cells upregu...

Supplementary Table 1: Mitochondrial antibodies spanning Complex(es) I–V from the OXPHOS chain including dilutions used, manufactures and catalogue numbers.

Objective: Detection of Alzheimer's disease (AD) prior to clinical inception will be paramount for introducing disease modifying treatments. We have begun collecting baseline characteristics of a community cohort for longitudinal assessment and testing of antecedent blood-based biomarkers. We describe the baseline visit from the first 131 subjects...

Gulf War Illness (GWI), which affects at least one fourth of the 700,000 veterans deployed to the Gulf War (GW), is characterized by persistent and heterogeneous symptoms, including pain, fatigue and cognitive problems. As a consequence, this illness remains difficult to diagnose. Rodent models have been shown to exhibit different symptomatic featu...

Principal component analysis for mice samples showing factors and total variance associated with each component, which were significantly associated with exposure based on MLM analyses. In mice, for PC 5 components were identified with PCA analysis, of which component 4 (p = 0.005) was significant for PB+PER exposure. For LPC 4 components were iden...

Total plasma levels for human samples, mice and rat model of PC, LPC, PE, LPE, PI and SM quantified by LC/MS analyses (all values are presented in μM ± SEM). Individual molecular species of each class were quantified by LC/MS and summed after lipidomeDB analyses to generate total lipid levels. *denotes significant p values for p<0.05. (DOCX)

Plasma levels for humans, mice and rat model of AA and DHA containing PC, LPC, PE and LPE species quantified by LC/MS analyses (all values are presented in μM ± SEM). No DHA containing LPE species were identified for the rat model, therefore ratio for AAtoDHA containing LPE species could not be determined.*denotes significant p values for p<0.05. (...

Principal component analysis for human samples showing factors and total variance associated with each component, which were significantly associated with exposure based on MLM analyses. In humans, for PC 8 components were identified with PCA analysis, of which components 2 (p = 0.005), 4 (p<0.001), 5 (p = 0.006) and 6 (p = 0.032) were significant...

Principal component analysis for rat samples showing factors and total variance associated with each component, which were significantly associated with exposure based on MLM analyses. In rats, for PC 3 components were identified with PCA analysis, of which component 1 (p = 0.017) and 2 (p<0.001) were significant for PB+PER+DEET and stress exposure...

Plasma levels for humans, mice and rat model of SFA, MUFA and PUFA containing PC, LPC, PE, LPE and PI species quantified by LC/MS analyses (all values are presented in μM ± SEM). *denotes significant p values for p<0.05. (DOCX)

Plasma levels for humans, mice and rat model of ether containing PC, LPC, PE and LPE species quantified by LC/MS analyses (all values are presented in μM ± SEM). *denotes significant p values for p<0.05. (DOCX)

Purpose: Long term consequences of combined pyridostigmine bromide and permethrin exposure in C57BL6/J mice using a well characterized mouse model of exposure to these Gulf War (GW) agents were explored at the protein level. Experimental design: We used orthogonal proteomic approaches to identify pathways that are chronically impacted in the mou...

This study was designed to explore the influence of apolipoprotein E (APOE) on blood phospholipids (PL) in predicting preclinical Alzheimer's disease (AD). Lipidomic analyses were also performed on blood from an AD mouse model expressing human APOE isoforms (EFAD) and five AD mutations and from 195 cognitively normal participants, 23 of who convert...

Neurophysiological and neurological dysfunction is usually experienced for a short period of time in patients with mild traumatic brain injury (mTBI). However, around 15 % of patients exhibit symptoms months after TBI. Phospholipid (PL) changes have been observed in plasma from mTBI patients at chronic stages, suggesting a role in TBI pathology. We...

Introduction: This systematic review examined the association between genetics and risk for sustaining a traumatic brain injury. Methods: Articles published in English from 1980 to July 2016 obtained from the online databases PubMed, PsycINFO®, MEDLINE®, EMBASE, and Web of Science. Results: 5,903 articles were identified, 77 underwent full-tex...

Primary objective: To investigate the status of the cerebrovasculature following repetitive mild traumatic brain injury (r-mTBI). Research design: TBI is a risk factor for development of various neurodegenerative disorders. A common feature of neurodegenerative disease is cerebrovascular dysfunction which includes alterations in cerebral blood flow...

Gulf War Illness (GWI) affects 25% of veterans from the 1990-1991 Gulf War (GW) and is accompanied by damage to the brain regions involved in memory processing. After twenty-five years, the chronic pathobiology of GWI is still unexplained. To address this problem, we examined the long-term consequences of GW exposures in an established GWI mouse mo...

Risk factors for concussion in active-duty military service members are poorly understood. The present study examined the association between self-reported concussion history and genetics [Apolipoprotein E (APOE), brain-derived neurotrophic factor (BDNF), and D2 dopamine receptor genes (DRD2)], trait personality measures (impulsive-sensation seekin...

Context • Telomeres are repeated deoxyribonucleic acid (DNA) sequences (TTAGGG) that are located on the 5' ends of chromosomes, and they control the life span of eukaryotic cells. Compelling evidence has shown that the length of a person's life is dictated by the limited number of times that a human cell can divide. The enzyme telomerase has been s...

Abstract Repetitive mild traumatic brain injury (r-mTBI) results in neuropathological and biochemical consequences in the human visual system. Using a recently developed mouse model of rmTBI, with control mice receiving repetitive anesthesia alone (r-sham) we assessed the effects on the retina and optic nerve using histology, immunohistochemistry,...

Integration of the identified dysregulated proteins into networks: Network #1—Cellular Assembly and Organization, Cellular Function and Maintenance, Tissue Development. Network was generated by Ingenuity Pathway Analysis (IPA). Twenty molecules were affected and IPA score was 46. Solid lines indicate direct interaction. Dashed lines indicate indire...

Canonical pathways associated with the effects of r-mTBI on optic nerve tissue at 3 weeks post injury. The list shows pathways that were significantly upregulated with log(p-value) >1.3 (equivalent to a p-value of <0.05). The radio value represents the number of molecules affected in the current data set for the particular pathway compared to the t...

MS/MS product ion identification of fatty acid composition and position for major molecular species detected. (PDF)

Integration of the identified dysregulated proteins into networks: Network #2 –Cancer, Lipid Metabolism, Molecular Transport. Fifteen molecules were affected and IPA score was 32. Solid lines indicate direct interaction. Dashed lines indicate indirect interactions. Red molecules were up-regulated and green molecules were down-regulated. The two mol...

Integration of the identified dysregulated proteins into networks: Network #4 -Behavior, Cell Morphology, Cellular Function and Maintenance. Six molecules were affected and IPA score was 10. Solid lines indicate direct interaction. Dashed lines indicate indirect interactions. Red molecules were up-regulated and green molecules were down-regulated....

Proteomic data for significantly up- or downregulated proteins at in optic nerve tissue at 3 weeks post injury. Proteins are listed ranked by the level of dysregulation: the down-regulated proteins sorted from the most downregulated to the least downregulated, while the unregulated sorted from the least upregulated to the most upregulated. (PDF)

Integration of the identified dysregulated proteins into networks: Network #3—Hereditary Disorder, Skeletal and Muscular Disorders, Cell Morphology. Twelve molecules were affected and IPA score was 12. Solid lines indicate direct interaction. Dashed lines indicate indirect interactions. Red molecules were up-regulated and green molecules were down-...

Phospholipid molecular species identified in optic nerve tissue at 3 weeks post injury by LC/MS. Mass estimate (m/z) for each species was obtained either in positive ion mode [M+H]+ or in negative ion mode [M-H]-. Mean values and standard deviations are expressed in μg/sample. Significant change is calculated by t-test and the level of significance...

Gulf War Illness (GWI) is a chronic multisymptom illness with a central nervous system component that includes memory impairment as well as neurological and musculoskeletal deficits. Previous studies have shown that in the First Persian Gulf War conflict (1990–1991) exposure to Gulf War (GW) agents, such as pyridostigmine bromide (PB) and permethri...

Schematic illustrating the battery of neurobehavioral testing undertaken from 11 days to 22.5 months (684 days) post exposure to GW agents, PB+PER.

Statistical analysis of dependent variables examined during Open Field Testing, 11 days post exposure to GW agents, PB+PER. Data was normally distributed, and therefore, One-way ANOVA analysis was used.

RAWM Post-hoc analyses (multiple comparisons testing using Least Significant Difference).

Background In addition to experiencing traumatic events while deployed in a combat environment, there are other factors that contribute to the development of posttraumatic stress disorder (PTSD) in military service members. This study explored the contribution of genetics, childhood environment, prior trauma, psychological, cognitive, and deploymen...

In the military population, there is high comorbidity between mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) due to the inherent risk of psychological trauma associated with combat. These disorders present with long-term neurological dysfunction and remain difficult to diagnose owing to their comorbidity and overlappin...