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Design and mathematical analysis of activating transcriptional amplifiers that enable modular temporal control in synthetic juxtacrine circuits

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synthetic and systems Biotechnology 2023年第4期8卷 654-672页

作者： Calvin Lam department of biochemistry and molecular biology University of Nebraska Medical CenterOmahaNE68198USA.

The ability to control mammalian cells such that they self-organize or enact therapeutic effects as desired has incredible *** only would it further our understanding of native processes such as development and the immune response,but it would also have powerful applications in medical fields such as regenerative medicine and *** control is typically obtained by synthetic circuits that use synthetic receptors,but control remains *** synthetic juxtacrine receptors(sJRs)are widely used as they are fully modular and enable spatial control,but they have limited gene expression amplification and temporal *** these are integral facets to cell control,I therefore designed transcription factor based amplifiers that amplify gene expression and enable unidirectional temporal control by prolonging duration of target gene *** a validated in silico framework for sJR signaling,I combined these amplifiers with sJRs and show that these sJR amplifier circuits can direct spatiotemporal patterning and improve the quality of self-organization.I then show that these circuits can improve chimeric antigen receptor(CAR)T cell tumor killing against various heterogenous antigen expression *** amplifiers are flexible tools that improve control over sJR based circuits with both basic and therapeutic applications.

关键词： synthetic biology synthetic development synthetic immunotherapy synNotch sNIPR Amplifiers self-organization Temporal control spatiotemporal control CAR T cell synthetic receptors

Impact of asialoglycoprotein receptor deficiency on the development of liver injury

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World Journal of Gastroenterology 2009年第10期15卷 1194-1200页

作者： serene ML Lee Carol A Casey Benita L McVicker departments of Internal Medicine and biochemistry & molecular biology University of Nebraska Medical Center Omaha NE 68105 United States Liver study unit Department of Veterans Affairs Medical Center and Departments of Internal Medicine and Biochemistry & Molecular Biology University of Nebraska Medical Center Omaha NE 68105 United States

The asialoglycoprotein （AsGP） receptor is a wellcharacterized hepatic receptor that is recycled via the common cellular process of receptor-mediated endocytosis （RME）. The RME process plays an integral part in the proper trafficking and routing of receptors and ligands in the healthy cell. Thus, the missorting or altered transport of proteins during RME is thought to play a role in several diseases associated with hepatocyte and liver dysfunction. Previously, we examined in detail alterations that occur in hepatocellular RME and associated receptor functions as a result of one particular liver injury, alcoholic liver disease （ALD）. The studies revealed profound ethanol- mediated impairments to the AsGP receptor and the RME process, indicating the importance of this receptor and the maintenance of proper endocytic events in normal tissue. To further clarify these observations, studies were performed utilizing knockout mice （lacking a functional AsGP receptor） to which were administered several liver toxicants. In addition to alcohol, we examined the effects following administration of anti- Fas （CD95） antibody, carbon tetrachloride （CCh） and lipopolysaccharide （LPs）/galactosamine. The results of these studies demonstrated that the knockout mice sustained enhanced liver injury in response to all of the treatments, as shown by increased indices of liver damage, such as enhancement of serum enzyme levels, histopathological scores, as well as hepatocellular death. Overall, the work completed to date suggests a possible link between hepatic receptors and liver injury. In particular, adequate function and content of the AsGP receptor may provide protection against various toxinmediated liver diseases.

关键词： Asialoglycoprotein receptor Asialoglycoproteinreceptor deficient mice Receptor-mediatedendocytosis Alcohol Carbon tetrachloride Anti-Fas Lipopolysaccharide/galactosamine Toxicant-induced liverinjury

Mucosal healing and inflammatory bowel disease:Therapeutic implications and new targets

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World Journal of Gastroenterology 2023年第7期29卷 1157-1172页

作者： Megan Lynn Otte Raju Lama Tamang Julia Papapanagiotou Rizwan Ahmad Punita Dhawan Amar B singh department of Pathology and Microbiology University of Nebraska Medical CenterOmahaNE 68198United States department of biochemistry and molecular biology University of Nebraska Medical CenterOmahaNE 68198United States

Mucosal healing(MH)is vital in maintaining homeostasis within the gut and protecting against injury and *** factors and signaling pathways contribute in a dynamic and coordinated manner to maintain intestinal homeostasis and mucosal regeneration/***,when intestinal homeostasis becomes chronically disturbed and an inflammatory immune response is constitutively active due to impairment of the intestinal epithelial barrier autoimmune disease results,particularly inflammatory bowel disease(IBD).Many proteins and signaling pathways become dysregulated or impaired during these pathological conditions,with the mechanisms of regulation just beginning to be ***,there remains a relative lack of broadly effective therapeutics that can restore MH due to the complexity of both the disease and healing processes,so tissue damage in the gastrointestinal tract of patients,even those in clinical remission,*** increased understanding of the molecular mechanisms of IBD and MH,tissue damage from autoimmune disease may in the future be ameliorated by developing therapeutics that enhance the body’s own healing *** this review,we introduce the concept of mucosal healing and its relevance in IBD as well as discuss the mechanisms of IBD and potential strategies for altering these processes and inducing MH.

关键词： Inflammation Injury/repair Mucosal healing Mucosal barrier Therapeutics Colitis

GDF15 promotes prostate cancer bone metastasis and colonization through osteoblastic CCL2 and RANKL activation

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Bone Research 2022年第1期10卷 150-164页

作者： Jawed Akhtar siddiqui Parthasarathy seshacharyulu sakthivel Muniyan Ramesh Pothuraju Parvez Khan Raghupathy Vengoji sanjib Chaudhary shailendra Kumar Maurya subodh Mukund Lele Maneesh Jain Kaustubh Datta Mohd Wasim Nasser surinder Kumar Batra department of biochemistry and molecular biology University of Nebraska Medical CenterOmahaNEUSA department of Pathology and Microbiology University of Nebraska Medical CenterOmahaNEUSA Fred&Pamela Buffett Cancer center University of Nebraska Medical CenterOmahaNE 68198-5870USA Eppley Institute for Research in Cancer and Allied Diseases University of Nebraska Medical CenterOmahaNEUSA

Bone metastases occur in patients with advanced-stage prostate cancer(PCa). The cell-cell interaction between PCa and the bone microenvironment forms a vicious cycle that modulates the bone microenvironment, increases bone deformities, and drives tumor growth in the bone. However, the molecular mechanisms of PCa-mediated modulation of the bone microenvironment are complex and remain poorly defined. Here, we evaluated growth differentiation factor-15(GDF15) function using in vivo preclinical PCa-bone metastasis mouse models and an in vitro bone cell coculture system. Our results suggest that PCa-secreted GDF15 promotes bone metastases and induces bone microarchitectural alterations in a preclinical xenograft model. Mechanistic studies revealed that GDF15 increases osteoblast function and facilitates the growth of PCa in bone by activating osteoclastogenesis through osteoblastic production of CCL2 and RANKL and recruitment of osteomacs. Altogether, our findings demonstrate the critical role of GDF15 in the modulation of the bone microenvironment and subsequent development of PCa bone metastasis.

关键词： GDF15 metastasis RANKL

Effect of ethanol on pro-apoptotic mechanisms in polarizedhepatic cells

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World Journal of Gastroenterology 2007年第37期13卷 4960-4966页

作者： Benita L McVicker Dean J Tuma Carol A Casey Liver study unit Department of Veterans Affairs Medical Center and departments of Internal Medicine and biochemistry & molecular biology University of Nebraska Medical Center Omaha NE 68105 United States

Chronic ethanol consumption is associated with serious and potentially fatal alcohol-related liver injuries such as hepatomegaly, alcoholic hepatitis and cirrhosis. Moreover, it has been documented that the clinical progression of alcohol-induced liver damage may be associated with an increase in hepatocellular death that involves apoptotic mechanisms. Although much information has been learned about the clinical manifestations associated with alcohol-related diseases, the search continues for a better understanding of the molecular and/or cellular mechanisms by which ethanol exerts its deleterious effects such as the induction of pro-apoptotic mechanisms and related cell damaging events. As part of the effort to enhance our understanding of those particular cellular pathways and mechanisms associated with ethanol toxicity, researchers over the years have utilized a variety of model systems. Recently, work has come forth demonstrating the utility of a hybrid cell line (WIF-B) as a cell culture model system for the study of alcohol-associated alterations in hepatocellular mechanisms. success with such emerging model systems could aid in the development of potential therapeutic treatments for the prevention of alcohol- induced apoptotic cell death that may ultimately serve as a significant target in delaying the onset and/or progression of clinical symptoms of alcohol-mediated liver disease. This review article summarizes the current understanding of ethanol-mediated modifications in cell survival and thus the promotion of pro-apoptotic events with emphasis on analyses made in various experimental model systems, particularly the more recently characterized WIF-B cell system.

关键词： Hepatoma hybrid cells Ethanol Apoptosis Fas receptor Caspase

Fibronectin: Functional character and role in alcoholic liver disease

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World Journal of Gastroenterology 2011年第20期17卷 2482-2499页

作者： Razia s Aziz-seible Carol A Casey department of Biomedical sciences Creighton University department of biochemistry and molecular biology University of Nebraska Medical Center985870 Nebraska Medical Center department of Internal Medicine University of Nebraska Medical Center 986350 Nebraska Medical Center The Liver study unit Omaha Veterans Affairs Medical Center

Fibronectins are adhesive glycoproteins that can be found in tissue matrices and circulating in various fluids of the body. The variable composition of fibronectin molecules facilitates a diversity of interactions with cell surface receptors that suggest a role for these proteins beyond the structural considerations of the extracellular matrix. These interactions implicate fibronectin in the regulation of mechanisms that also determine cell behavior and activity. The two major forms, plasma fibronectin (pFn) and cellular fibronectin (cFn), exist as balanced amounts under normal physiological conditions. However, during injury and/or disease, tissue and circulating levels of cFn become disproportionately elevated. The accumulating cFn, in addition to being a consequence of prolonged tissue damage, may in factstimulate cellular events that promote further damage. In this review, we summarize what is known regarding such interactions between fibronectin and cells that may influence the biological response to injury. We elaborate on the effects of cFn in the liver, specifically under a condition of chronic alcohol-induced injury. studies have revealed that chronic alcohol consumption stimulates excess production of cFn by sinusoidal endothelial cells and hepatic stellate cells while impairing its clearance by other cell types resulting in the build up of this glycoprotein throughout the liver and its consequent increased availability to influence cellular activity that could promote the development of alcoholic liver disease. We describe recent findings by our laboratory that support a plausible role for cFn in the promotion of liver injury under a condition of chronic alcohol abuse and the implications of cFn stimulation on the pathogenesis of alcoholic liver disease. These findings suggest an effect of cFn in regulating cell behavior in the alcohol-injured liver that is worth further characterizing not only to gain a more comprehensive understanding of the role this r

关键词： Fibronectin Liver disease Alcoholic liver disease Endocytosis Cellular fibronectin

Therapeutic implications of sARs-CoV-2 dysregulation of the gutbrain-lung axis

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World Journal of Gastroenterology 2021年第29期27卷 4763-4783页

作者： samuel D Johnson Omalla A Olwenyi Namita Bhyravbhatla Michellie Thurman Kabita Pandey Elizabeth A Klug Morgan Johnston shetty Ravi Dyavar Arpan Acharya Anthony T Podany Courtney V Fletcher Mahesh Mohan Kamal singh siddappa N Byrareddy department of Pathology and Microbiology University of Nebraska Medical CenterOmahaNE 68198United States department of Pharmacology and Experimental neuroscience University of Nebraska Medical CenterOmahaNE 68198United States Antiviral Pharmacology Laboratory University of Nebraska Medical Center(UNMC)Center for Drug DiscoveryOmahaNE 68198United States southwest National Primate Research center Texas Biomedical Research InstituteSan AntonioTX 78227United States department of molecular Microbiology and Immunology and Bond Life sciences center University of MissouriColumbiaMO 65212United States department of Genetics Cell Biology and AnatomyUniversity of Nebraska Medical CenterOmahaNE 68198United States department of biochemistry and molecular biology University of Nebraska Medical CenterOmahaNE 68198United States

The emergence and rapid spread of novel severe acute respiratory syndrome coronavirus 2(sARs-CoV-2)has caused over 180 million confirmed cases resulting in over 4 million deaths worldwide with no clear end in sight for the coronavirus disease 19(COVID-19)*** sARs-CoV-2 exposed individuals experience mild to moderate symptoms,including fever,cough,fatigue,and loss of smell and ***,many individuals develop pneumonia,acute respiratory distress syndrome,septic shock,and multiorgan *** addition to these primarily respiratory symptoms,sARs-CoV-2 can also infiltrate the central nervous system,which may damage the blood-brain barrier and the neuron's *** inflammation and neurodegeneration in the brain stem can further prevent efferent signaling to cranial nerves,leading to the loss of anti-inflammatory signaling and normal respiratory and gastrointestinal ***,sARs-CoV-2 can infect enterocytes resulting in gut damage followed by microbial dysbiosis and translocation of bacteria and their byproducts across the damaged epithelial *** a result,this exacerbates pro-inflammatory responses both locally and systemically,resulting in impaired clinical *** evidence has highlighted the complex interactions that mutually modulate respiratory,neurological,and gastrointestinal *** this review,we discuss the ways sARs-CoV-2 potentially disrupts the gut-brain-lung *** further highlight targeting specific responses to sARs-CoV-2 for the development of novel,urgently needed therapeutic ***,we propose a prospective related to the individuals from Low-and Middle-Income ***,the underlying propensity for heightened gut damage/microbial translocation is likely to result in worse clinical outcomes during this COVID-19 pandemic.

关键词： sARs-CoV-2 Gut Microbiome Lungs Brain Therapeutics

RNA INTERFERENCE OF ANneXIN II GEne IN PC3 CELLs BY usING sMALL INTERFERENCE RNA sYNTHEsIZED WITH IN VITRO TRANsCRIPTION

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Chinese medical sciences Journal 2007年第1期22卷 33-37页

作者： Ya-wei Yuan Ai-min sun Ying Lui Long-hua Chen Banerjee A. G department of Radiotherapy Nanfang Hospital of Nanfang Medical University Guangzhou 510515 department of biochemistry and molecular biology University. of Nebraska Medical Center Omaha NE 68198-7835 USA

Objective To silence annexin Ⅱ gene expression by using small interference RNA （siRNA） in prostate cancer cell line PC3. Methods For in vitro transcription, four sequences of 29-nucleotide DNA template oligonucleotides were designed, and one pair of the sequences were complementary to annexin Ⅱ gene. The other pair was negative control. The 8 nucleotides at the 3＇ end of each oligonucleotide were complementary to the T7 Promoter Primer. The sense and anti-sense siRNA templates were transcribed by T7 RNA polymerase and the resulting RNA transcripts were hybridized to create dsRNA. The siRNA was transfected into prostate cancer cell PC3. For assaying the efficiency of siRNA, confocal microscopy, Northern blotting, and Western blotting were employed to examine the expression of annexin Ⅱ protein and its mRNA. ^3H thymidine was used to measure DNA synthesis. Results The siRNA sequence specific to annexin Ⅱ gene was capable of inhibiting the expression of annexin Ⅱ protein and its mRNA. And cellular DNA synthesis was significantly reduced in siRNA transfected cells.Conclusions The protocol for the synthesis of siRNA by T7 RNA polymerase is feasible. Annexin Ⅱ might be involved in DNA synthesis.

关键词： small interference RNA gene silencing annexin Ⅱ prostate cancer cell

Lysosome and proteasome dysfunction in alcohol-induced liver injury

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Liver Research 2019年第3期3卷 191-205页

作者： Terrence M.Donohue.Jr Natalia A.Osna Kusum K.Kharbanda Paul G.Thomes Research service Department of Veterans AffairsNebraska-Western Iowa Health Care SystemOmahaNEUSA department of Internal Medicine Section of Gastroenterology and HepatologyUniversity of Nebraska Medical CenterOmahaNEUSA department of biochemistry and molecular biology University of Nebraska Medical CenterOmahaNEUSA department of Pharmacology and Experimental neuroscience University of Nebraska Medical CenterOmahaNEUSA College of Public Health University of Nebraska Medical CenterOmahaNEUSA

The review describes research findings on the influence of alcohol consumption on two crucial catabolic systems in hepatocytes:the lysosome and the ubiquitin-proteasome system(uPs).The lysosome is a membrane-bound organelle that degrades all aging and/or damaged organelles and hydrolyzes all forms of *** uPs is mostly *** carries out the majority of its functions in the soluble portion of the cytoplasm(cytosol)and degrades nearly all intracellular proteins,particularly those with short half-lives,so that their levels are tightly *** review will briefly discuss the epidemiology of alcohol abuse and the spectrum of alcohol-induced liver disease(AILD).We will explain why ethanol(EtOH)metabolism,but not EtOH alone,is ***,we will summarize how heavy drinking alters hepatic catabolic systems,resulting in liver enlargement that develops from hepatocyte swelling due,in part,to aberrant accumulation of undegraded lipid droplets(steatosis)and undegraded proteins(proteopathy).Our detailed description of each catabolic system will highlight its discoverer(s)and emphasize each system’s *** important,we will review the evidence that chronic EtOH consumption disrupts hepatic lysosome biogenesis and inhibits the uPs by impeding hepatic proteasome *** will become evident that each of these EtOH-induced defects has far-reaching functional ***,we will describe current and potential therapeutic interventions for alleviating EtOH-induced liver *** most effective intervention is the cessation of EtOH ***,there are other potential approaches using natural or synthetic compounds that activate autophagy or the proteasome to enhance the degradation of accumulated lipid droplets or proteins,respectively,which could alleviate *** approaches,now in their early stages of investigation,will also be discussed in this review.

关键词： Alcohol Lysosome Proteasome Ethanol Liver Proteostasis Lipostasis Alcohol-induced liver disease(AILD)