Medicine and Health Sciences Commons^™

Cellular Origins Of Egfr-Driven Lung Cancer Cells Determine Sensitivity To Therapy, Fan Chen, Jinpeng Liu, Robert M. Flight, Kassandra J. Naughton, Alexsandr Lukyanchuk, Abigail R Edgin, Xiulong Song, Haikuo Zhang, Kwok-Kin Wong, Hunter N. B. Moseley, Chi Wang, Christine F. Brainson

Toxicology and Cancer Biology Faculty Publications

Targeting the epidermal growth factor receptor (EGFR) with tyrosine kinase inhibitors (TKIs) is one of the major precision medicine treatment options for lung adenocarcinoma. Due to common development of drug resistance to first- and second-generation TKIs, third-generation inhibitors, including osimertinib and rociletinib, have been developed. A model of EGFR-driven lung cancer and a method to develop tumors of distinct epigenetic states through 3D organotypic cultures are described here. It is discovered that activation of the EGFR T790M/L858R mutation in lung epithelial cells can drive lung cancers with alveolar or bronchiolar features, which can originate from alveolar type 2 (AT2) cells …

Myeloid Arginase 1 Insufficiency Exacerbates Amyloid-Β Associated Neurodegenerative Pathways And Glial Signatures In A Mouse Model Of Alzheimer’S Disease: A Targeted Transcriptome Analysis, Chao Ma, Jerry B. Hunt, Andrii Kovalenko, Huimin Liang, Maj-Linda B. Selenica, Michael B. Orr, Bei Zhang, John C. Gensel, David J. Feola, Marcia N. Gordon, Dave Morgan, Paula C. Bickford, Daniel C. Lee

Sanders-Brown Center on Aging Faculty Publications

Brain myeloid cells, include infiltrating macrophages and resident microglia, play an essential role in responding to and inducing neurodegenerative diseases, such as Alzheimer’s disease (AD). Genome-wide association studies (GWAS) implicate many AD casual and risk genes enriched in brain myeloid cells. Coordinated arginine metabolism through arginase 1 (Arg1) is critical for brain myeloid cells to perform biological functions, whereas dysregulated arginine metabolism disrupts them. Altered arginine metabolism is proposed as a new biomarker pathway for AD. We previously reported Arg1 deficiency in myeloid biased cells using lysozyme M (LysM) promoter-driven deletion worsened amyloidosis-related neuropathology and behavioral impairment. However, …

Nmr Methods For Determining Lipid Turnover Via Stable Isotope Resolved Metabolomics, Penghui Lin, Li Dai, Daniel R. Crooks, Leonard M. Neckers, Richard M. Higashi, Teresa W.-M. Fan, Andrew N. Lane

Center for Environmental and Systems Biochemistry Faculty Publications

Lipids comprise diverse classes of compounds that are important for the structure and properties of membranes, as high-energy fuel sources and as signaling molecules. Therefore, the turnover rates of these varied classes of lipids are fundamental to cellular function. However, their enormous chemical diversity and dynamic range in cells makes detailed analysis very complex. Furthermore, although stable isotope tracers enable the determination of synthesis and degradation of complex lipids, the numbers of distinguishable molecules increase enormously, which exacerbates the problem. Although LC-MS-MS (Liquid Chromatography-Tandem Mass Spectrometry) is the standard for lipidomics, NMR can add value in global lipid analysis and …

Differential Leukocyte And Platelet Profiles In Distinct Models Of Traumatic Brain Injury, William Brad Hubbard, Meenakshi Banerjee, Hemendra J. Vekaria, Kanakanagavalli Shravani Prakhya, Smita Joshi, Qingjun Wang, Kathryn E. Saatman, Sidney W. Whiteheart, Patrick G. Sullivan

Spinal Cord and Brain Injury Research Center Faculty Publications

Traumatic brain injury (TBI) affects over 3 million individuals every year in the U.S. There is growing appreciation that TBI can produce systemic modifications, which are in part propagated through blood–brain barrier (BBB) dysfunction and blood–brain cell interactions. As such, platelets and leukocytes contribute to mechanisms of thromboinflammation after TBI. While these mechanisms have been investigated in experimental models of contusion brain injury, less is known regarding acute alterations following mild closed head injury. To investigate the role of platelet dynamics and bioenergetics after TBI, we employed two distinct, well-established models of TBI in mice: the controlled cortical impact (CCI) …

Mitochondrial Oxidative And Nitrosative Stress And Alzheimer Disease, D. Allan Butterfield, Debra Boyd-Kimball

Chemistry Faculty Publications

Oxidative and nitrosative stress are widely recognized as critical factors in the pathogenesis and progression of Alzheimer disease (AD) and its earlier stage, amnestic mild cognitive impairment (MCI). A major source of free radicals that lead to oxidative and nitrosative damage is mitochondria. This review paper discusses oxidative and nitrosative stress and markers thereof in the brain, along with redox proteomics, which are techniques that have been pioneered in the Butterfield laboratory. Selected biological alterations in—and oxidative and nitrosative modifications of—mitochondria in AD and MCI and systems of relevance thereof also are presented. The review article concludes with a section …

The Bach1/Nrf2 Axis In Brain In Down Syndrome And Transition To Alzheimer Disease-Like Neuropathology And Dementia, Marzia Perluigi, Antonella Tramutola, Sara Pagnotta, Eugenio Barone, D. Allan Butterfield

Chemistry Faculty Publications

Down syndrome (DS) is the most common genetic cause of intellectual disability that is associated with an increased risk to develop early-onset Alzheimer-like dementia (AD). The brain neuropathological features include alteration of redox homeostasis, mitochondrial deficits, inflammation, accumulation of both amyloid beta-peptide oligomers and senile plaques, as well as aggregated hyperphosphorylated tau protein-containing neurofibrillary tangles, among others. It is worth mentioning that some of the triplicated genes encoded are likely to cause increased oxidative stress (OS) conditions that are also associated with reduced cellular responses. Published studies from our laboratories propose that increased oxidative damage occurs early in life in …

Method And System For Identification Of Metabolites Using Mass Spectra, Hunter N. B. Moseley, William J. Carreer, Joshua Mitchell, Robert M. Flight

Molecular and Cellular Biochemistry Faculty Patents

A method and system is provided for mass spectrometry for identification of a specific elemental formula for an unknown compound which includes but is not limited to a metabolite. The method includes calculating a natural abundance probability (NAP) of a given isotopologue for isotopes of non-labelling elements of an unknown compound. Molecular fragments for a subset of isotopes identified using the NAP are created and sorted into a requisite cache data structure to be subsequently searched. Peaks from raw spectrum data from mass spectrometry for an unknown compound. Sample-specific peaks of the unknown com- pound from various spectral artifacts in …

Phenylethynyl-Substituted Benzenes And Heterocycles For The Treatment Of Cancer, David S. Watt, Chunming Liu, Vitaliy M. Sviripa, Wen Zhang, Markos Leggas

Molecular and Cellular Biochemistry Faculty Patents

Halogenated phenylethynyl-substituted heterocycles that possess either an N-alkylamino or N,N-dialkylamino group attached to the heterocycle or halogenated phenylethynyl-substituted benzenes that a nitrogen-containing heterocycle attached to the benzene inhibit the proliferation cancer cells and are useful antineoplastic agents.

Antisense Oligonucleotide Modulators Of Serotonin Receptor 2c And Uses Thereof, Stefan Stamm, Manli Shen, Serene Josiah

Molecular and Cellular Biochemistry Faculty Patents

The present invention provides, among other things, oligonucleotide modulators of human 5′-HT2C receptor (HTR2C) and improved methods and composition for treating HTR2C-related diseases, disorders or conditions based on such modulators. In particular, oligonucleotides modulators according to the invention target specific regions in the Exon V/Intron V junction of the human HTR2C pre-mRNA and drive expression of HTR2C Vb splice isoform, leading to increased generation of non-edited strong HTR2C receptor and enhanced serotonin receptor activity.

Arylquinoline And Analog Compounds And Use Thereof To Treat Cancer, David S. Watt, Chunming Liu, Vivek M. Rangnekar, Vitaliy M. Sviripa, Ravshan Burikhanov, Wen Zhang

Molecular and Cellular Biochemistry Faculty Patents

The subject technology relates to arylquinoline compounds and their use for treating cancer or cancer metastasis. The compounds of the subject technology promote cells to secrete a pro-apoptotic tumor suppressor, i.e., prostate apoptosis response-4 (Par-4), which in turn promote apoptosis in cancer cells or metastatic cells.

Compounds And Method Of Use As Anti-Infection Compounds And Therapeutic Agents To Regulate Cholesterol Metabolism, Joseph Chappell, Tom D. Niehaus, Kristin Brooke Linscott

Molecular and Cellular Biochemistry Faculty Patents

A compound is provided which comprises at least a portion of an amino acid linker-domain from squalene synthase. In alternative forms, the compound can include the amino-acid linker-domain from various fungus, including S. cerevisiae or the compound can be the functional equivalent and/or mimics an amino acid linker-domain from squalene synthase. A pharmaceutical composition includes the compound and may further include a pharmaceutical carrier. A method is provided for treating or controlling cholesterol metabolism and ergosterol metabolism in non-fungal organisms. One method includes a therapeutic treatment in humans by administering a therapeutically effective amount of the compound or pharmaceutical composition, …

Antisense Oligonucleotide Modulators Of Serotonin Receptor 2c And Uses Thereof, Stefan Stamm, Manli Shen, Serene Josiah

Molecular and Cellular Biochemistry Faculty Patents

The present invention provides, among other things, oligonucleotide modulators of human 5'-HT2C receptor (HTR2C) and improved methods and composition for treating HTR2C-related diseases, disorders or conditions based on such modulators. In particular, oligonucleotides modulators according to the invention target specific regions in the Exon V/Intron V junction of the human HTR2C pre-mRNA and drive expression of HTR2C Vb splice isoform, leading to increased generation of non-edited strong HTR2C receptor and enhanced serotonin receptor activity.

Glucan Phosphatase Variants For Starch Phosphorylation, Matthew S. Gentry, Craig Vander Kooi

Molecular and Cellular Biochemistry Faculty Patents

Glucan phosphatase nucleotide or polypeptide variants of the presently-disclosed subject matter can alter the biophysical properties of starch in vitro or in planta, as well as the total starch biomass production in planta as compared to plants expressing wild-type glucan phosphatases. Plants producing the polypeptide variants of the presently-disclosed subject matter can have increased starch accumulation, increased starched biomass, and/or starch having desired biophysical properties. A method of the presently-disclosed subject matter for producing altered starch includes providing a plant that produces a glucan phosphatase polypeptide variant that comprises an amino acid mutation and collecting starch from the plant.

Molecular Genetics Of Ms4a6a And Alzheimer's Disease, Ryan Harpole

Lewis Honors College Capstone Collection

Increased Alzheimer’s disease (AD) risk has previously been associated with a SNP called rs610932 near the gene MS4A6A. The goal of this experiment was to quantify the expression of two MS4A6A isoforms in the brains of AD and non-AD subjects, particularly as a function of rs610932 genotype. According to an article titled “Alzheimer’s Disease Susceptibility Variants in the MS4A6A Gene are Associated with Altered Levels of MS4A6A Expression in Blood”, MS4A6A has four different isoforms that have been reported to be differentially expressed in the blood of AD subjects compared to non-AD subjects (Petroula et al., 2014). After statistically …

Thermophilic Phosphatases And Methods For Processing Starch Using The Same, Matthew S. Gentry, Craig W. Vander Kooi

Molecular and Cellular Biochemistry Faculty Patents

The presently-disclosed subject matter includes thermophilic glucan phosphatase polypeptides. In some embodiments the polypeptide includes non-native laforin polypeptides, or fragments and/or variants thereof, and in some instances the polypeptide can alter the biophysical properties of starch in vitro or in planta. The presently-disclosed subject matter also includes isolated polynucleotides encoding the present polypeptides, methods for processing starch by exposing starch to the present polypeptides, and methods for making the present polypeptides.

Amyloid Peptide Inactivating Enzyme To Treat Alzheimer's Disease Peripherally, Louis B. Hersh, Hanjun Guan

Molecular and Cellular Biochemistry Faculty Patents

Methods for treatment and/or prevention of Alzheimer's disease comprising inactivating peripheral AP in serum to a reduce A(3 in the brain. Methods comprise expression of amyloid peptide inactivating enzyme on bone marrow cells; and coupling of amyloid peptide inactivating enzyme to hematopoietic cells.

Stilbene Analogs And Methods Of Treating Cancer, David Watt, Chunming Liu, Vitaliy M. Sviripa, Wen Zhang

Molecular and Cellular Biochemistry Faculty Patents

Stilbene analogs and pharmaceutical compositions that are useful for the treatment of various cancers, including without limitation, colorectal cancer (CRC) and breast cancer are disclosed.

For the complete abstract, please download this patent.

Mutant Insulin Degrading Enzyme And Methods Of Use, David W. Rodgers, Louis B. Hersh, Nicholas Noinaj, Eun Suk Song

Molecular and Cellular Biochemistry Faculty Patents

In one aspect, the present invention provides an isolated mutant insulin degrading enzyme (IDE) having an amino acid sequence that is at least 90% identical to SEQ ID NO:1 over its entire length and comprises at least one amino acid substitution at any of amino acid residues 332, 339, 341, 359, 360, 361, 374, 429, 609, 898, 899 or 901 of the sequence. The mutant IDE has a differential activity relative to that of wild-type IDE. Also provided is a polynucleotide encoding the polypeptide of the invention.

Targeting Astrocytes Ameliorates Neurologic Changes In A Mouse Model Of Alzheimer's Disease, Jennifer L. Furman, Diana M. Sama, John C. Gant, Tina L. Beckett, M. Paul Murphy, Adam D. Bachstetter, Linda J. Van Eldik, Christopher M. Norris

Pharmacology and Nutritional Sciences Faculty Publications

Astrocytes are the most abundant cell type in the brain and play a critical role in maintaining healthy nervous tissue. In Alzheimer's disease (AD) and most other neurodegenerative disorders, many astrocytes convert to a chronically "activated" phenotype characterized by morphologic and biochemical changes that appear to compromise protective properties and/or promote harmful neuroinflammatory processes. Activated astrocytes emerge early in the course of AD and become increasingly prominent as clinical and pathological symptoms progress, but few studies have tested the potential of astrocyte-targeted therapeutics in an intact animal model of AD. Here, we used adeno-associated virus (AAV) vectors containing the astrocyte-specific …

Scavenger Receptor Cd36 Expression Contributes To Adipose Tissue Inflammation And Cell Death In Diet-Induced Obesity, Lei Cai, Zhen Wang, Ailing Ji, Jason M. Meyer, Deneys R. Van Der Westhuyzen

Internal Medicine Faculty Publications

OBJECTIVE: The enlarged adipose tissue in obesity is characterized by inflammation, including the recruitment and infiltration of macrophages and lymphocytes. The objective of this study was to investigate the role of the scavenger receptor CD36 in high fat diet-induced obesity and adipose tissue inflammation and cell death.

EXPERIMENTAL APPROACH: Obesity and adipose tissue inflammation was compared in CD36 deficient (CD36 KO) mice and wild type (WT) mice fed a high fat diet (60% kcal fat) for 16 weeks and the inflammatory response was studied in primary adipocytes and macrophages isolated from CD36 KO and WT mice.

RESULTS: Compared to WT …

Insulin Degrading Enzyme Assays For Treatment Of Alzheimer's Disease, Louis B. Hersh

Molecular and Cellular Biochemistry Faculty Patents

Estrogen has been shown to increase the expression and activity of amyloid peptide inactivating enzymes in the brain. Peptides have been shown to increase the activity of an amyloid peptide inactivating enzyme. Methods of identifying compounds for, and methods of treating patients with, Alzheimer's Disease is disclosed.

Antibodies And Unnatural Substrates Of Prenylation Enzymes For Use In Detecting And Isolating Prenylated Proteins, H. Peter Spielmann, Douglas A. Andres

Molecular and Cellular Biochemistry Faculty Patents

Unnatural substrates of prenylation enzymens and antibodies that recognize unique moieties of prenylated proteins, which unique moieties are transferred from the unnatural substrates are used for detecting and isolating prenylated proteins, and for screening for inhibitors of prenylation enzymes.

Crystallization And Structure Of A Plant Peptide Deformylase, Robert L. Houtz, David W. Rodgers, Lynnette M. A. Dirk, Mark A. Williams

Molecular and Cellular Biochemistry Faculty Patents

This invention relates to the crystal structure of a plant peptide deformylase polypeptide and methods of using the structure to design compounds that modulate the activity of the polypeptide.

Seventeen Amino Acid Peptide (Peptide P) For Treating Ischemia And Reperfusion Injury, Peter R. Oeltgen, Mark S. Kindy

Molecular and Cellular Biochemistry Faculty Patents

Peptide P, having the amino acid sequence Tyr-D-Ala-Phe-Ala-Asp-Val-Ala-Ser-Thr-Ile-Gly-Asp-Phe-His-Ser-Ile-NH2-SEQ ID NO:1, is useful to treat ischemia.

Protection Against Ischemia And Reperfusion Injury, Peter R. Oeltgen, Paul D. Bishop, Mark S. Kindy, Juan A. Sanchez

Molecular and Cellular Biochemistry Faculty Patents

A compound and method for using the compound to reduce injury associated with ischemia and reperfusion of mammalian organs such as the heart. The compound, either Deltorphin A and/or Dermorphin H, may be administered as part of a preconditioning strategy which reduces the extent of injury and improves organ function following cessation and restoration of blood flow. The compound may be used in preparation for planned ischemia or in a prophylactic manner in anticipation of further ischemic events.

Protection Against Ischemia And Reperfusion Injury, Peter R. Oeltgen, Paul D. Bishop, Mark S. Kindy, Juan A. Sanchez

Molecular and Cellular Biochemistry Faculty Patents

A compound and method for using compound-D SEQ ID NO:1 to reduce injury associated with ischemia and reperfusion of mammalian organs such as the heart. The compound may be administered as part of a preconditioning strategy which reduces the extent of injury and improves organ function following cessation and restoration of blood flow. The compound may be used in preparation for planned ischemia or in a prophylactic manner in anticipation of further ischemic events.

Seventeen Amino Acid Peptide (Peptide P) For Treating Ischemia And Reperfusion Injury, Peter R. Oeltgen, Mark S. Kindy

Molecular and Cellular Biochemistry Faculty Patents

Peptide P, having the amino acid sequence Tyr-D-Ala-Phe-Ala-Asp-Val-Ala-Ser-Thr-Ile-Gly-Asp-Phe-Phe-His-Ser-Ile-NH2, is useful to treat ischemia.

Protection Against Ischemia And Reperfusion Injury, Peter R. Oeltgen, Paul D. Bishop, Mark S. Kindy, Juan A. Sanchez

Molecular and Cellular Biochemistry Faculty Patents

A compound and method for using the compound to reduce injury associated with ischemia and reperfusion of mammalian organs such as the heart. The compound may be administered as part of a preconditioning strategy which reduces the extent of injury and improves organ function following cessation and restoration of blood flow. The compound may be used in preparation for planned ischemia or in a prophylactic manner in anticipation of further ischemic events.

Method For Treating Ischemia, Peter R. Oeltgen, Mark S. Kindy, Paul D. Bishop

Molecular and Cellular Biochemistry Faculty Patents

A method for treating ischemia by administering deltorphins to a mammal. Deltorphin I SEQ ID NO:1, delntorphin II SEQ ID NO:2 or combinations of deltorphins I SEQ ID NO:1 and II SEQ ID NO:2 may be administered. A deltorphin concentration of about 0.5-20 mg/kg body weight, or alternatively a lower concentration of about 1-1000 μg/kg body weight of the mammal in a physiologically acceptable formulation is administered up to four hours after an ischemic episode. Deltorphins may also be administered prior to or concurrently with onset of ischemia. Cerebral or spinal cord ischemia or ischemic heart disease may be treated …

Farnesyl Pyrophosphate Analogs, Hans Peter Spielmann, Douglas A. Andres, Kareem A.H. Chehade

Molecular and Cellular Biochemistry Faculty Patents

The post-translational addition of a farnesyl moiety to the Ras oncoprotein is essential for its membrane localization and is required for both its biological activity and ability to induce malignant transformation. The present invention describes design and synthesis of a farnesylpyrophosphate (FPP) analog, 8-anilinogeranyl pyrophosphate (AGPP) that is transferred to Ras by farnesyltransferase (FTase), in which the ω-terminal isoprene unit of the farnesyl group has been replaced with an aniline functionality. AGPP potently inhibited FTase activity in vitro (IC₅₀=0.6 μM) and is highly selective showing little inhibitory activity against either geranylgeranyl-protein transferase type I (GGTase I) (IC_{50 …}