• Health Disparities in Acute Outcomes of Life-threatening Injury

      NeSmith, Elizabeth Grooms; Department of Nursing (2007-12)
      Health disparities have been documented in nearly all-leading causes of death. It is unknown if health disparities also exist in acute outcomes of life-threatening injury. The overall research question for this dissertation was, “Do health disparities exist in acute outcomes of life-threatening injury?”. Three studies were conducted: a state of science, a validity study, and a descriptive study. The state of the science showed that only 4 of 352 studies reported disparities, while 3 of 352 studies reported no disparities. The validity study was a retrospective chart review and showed that the instrument used to measure systemic inflammatory response syndrome was valid in predicting intensive care unit length of stay (F = 15.83) p < .0001. Caucasian race also predicted intensive care unit length of stay (F = 9.7) p = .002. When combined with race, the systemic inflammatory response syndrome instrument explained more variance (R2 = .15) in intensive care unit length of stay than either variable alone (F = 7.7) p = .006. The descriptive study utilized the same data set from the validity study, and showed fewer occurrences of systemic inflammatory response syndrome in African Americans than in Caucasians (T = 9949.5) p = .04; in adults 30-44 years old than in adults 18-29 (T = 13,654) p = .04; and in ethyl alcohol users than in all other substance users (X2 = 7.85) p = .005. There was less severity of systemic inflammatory response syndrome in females than in males (T = 7,491.5) p = .03; and in marijuana users than in all other substance users (T = 3,117) p = .02. More severity of systemic inflammatory response syndrome was found among ethyl alcohol users than in all other substance users (T = 2,667) p = .0008. Results support that health disparities exist among different patient groups according to race, age, sex, and substance use for systemic inflammatory response syndrome. More research is needed to determine if these disparities translate to increased risk for poor outcomes. Implications for practice include increased vigilance of different patient groups based on occurrence and severity of systemic inflammatory response syndrome.
    • Health Needs of Older Adult Women in the Rural Environment

      Conway, Mary Ann; Department of Nursing (1983-12)
      This study addressed the following research questions: 1). What are the perceived health needs of older warren in the rural environment? 2) Are. there correlations between perceived health needs .and demographic ' ' . . and sociological variables related to. these needs? The descriptive survey utilized a purposive convenience sample of 14 wanen between the I ages of 66 and 79 •. Half were black, half were white. In-hare interviews were c?nducted by the investigator utilizing. a structured . inter...: view questionnaire to collect demographic data and infonnation regarding ·five ·areas of ·health need: . health· condition, functional status,· social interaction, accessibility o~ health care and service· need •. findings revealed that rrore than half the subjects were widowed. Half ·lived alone. ·.The majority ·had inadequate incanes. A relationship between race a.n.d incane, education, self-rated health, life satisfaction, health condition and functional status was noted.. The ma.jority of the health needs. related to physical functioning and chronic' conditions. Blacks and ~ose 75 or over had rrore·chronic conditions, recent illness and physical ·symptoms and used rrore p~escription.drugs than did whites. Blacks and those under 75 reported rrore activity limitations and disability days than whites and those 75 or over. The black ~espo!fdents and. those 75 or over were less healthy than ·the whites and those under 75. The potential for accidental misuse of rredications is increased among this sample as is the possibility of physical· canplications due to inactivity and lack of exercise. A need . for· health educatio:n programs and health prorrotion, maintenance ~d restorative services targeted to this· population ~s noted.
    • Health-Promoting Lifestyles of Women with HIV Disease

      Carr, Rebecca L.; Department of Physiological and Technological Nursing (1997-04)
      Women are one of the fastest growing risk groups for HIV infection in the United States, but little is known about how women manage the problems and concerns commonly faced by individuals who are HIV positive. HIV disease results in compromised lifestyles for women as they cope with physiological and psychosocial problems that accompany this disease. The purpose of this focused ethnography was to explore health-promoting lifestyles of women with HIV disease. Research questions guiding this study were: 1) What do women with HIV disease believe they can do to enhance and/or maintain their health after diagnosis? and 2) How do women promote and maintain their health and well-being? Purposive sampling was used to obtain nine European American participants between the ages of 27 and 52 years. These participants were recruited from the southeastern United States. Semi-structured interviews and observation participation were used to obtain data. The majority of participants were interviewed three times. Observation participation occurred during interviews, at conferences, and volunteer group meetings attended by the researcher and the participants. Data analysis was concurrent with data collection enabling the researcher to confirm her interpretations with the participants. Three major themes were identified: 1) Reaching out to others, 2) Searching for meaning, and 3) Buying time. These themes constituted a health-promoting lifestyle that enabled women to adjust to the change in their identity from a healthy person to a person with HIV disease. Initially, women focused on restoring their well-being, but later initiated changes to enhance, maintain, and maximize their health.
    • Health-Promoting Lifestyles of Women with HIV Disease

      Carr, Rebecca Lamb; School of Graduate Studies (1997-04)
      Women are one of the fastest growing risk groups for HIV infection in the United States, but little is known about how women manage the problems and concerns commonly faced by individuals who are HIV positive. HIV disease results in compromised lifestyles for women as they cope with physiological and psychosocial problems that accompany this disease. The purpose of this focused ethnography was to explore health-promoting lifestyles of women with HIV disease. Research questions guiding this study were: 1) What do women with HIV disease believe they can do to enhance and/or maintain their health after diagnosis? and 2) How do women promote and maintain their health and well-being? Purposive sampling was used to obtain nine European American participants between the ages of 27 and 52 years. These participants were recruited from the southeastern United States. Semi-structured interviews and observation participation were used to obtain data. The majority of participants were interviewed three times. Observation participation occurred during interviews, at conferences; and volunteer group meetings attended by the researcher and the participants. Data analysis was concurrent with data collection enabling the researcher to confirm her interpretations with the participants. Three major themes were identified: 1) Reaching out to others, 2) Searching for meaning, and 3) Buying time. These themes constituted a health-promoting lifestyle that enabled women to adjust to the change in their identity from a healthy person to a person with HIV disease. Initially, women focused on restoring their well-being, but later initiated changes to enhance, maintain, and maximize their health. INDEX WORDS: HIV disease, Women, Stigma, Self-in-relation, Health-promoting lifestyle, Health behavior, Health belief
    • Heat shock protein 70 promotes HCC by modulating DNA-damage response, MAPK/ERK signaling and cellular senescence

      Wang, Yan; Department of Biochemistry and Molecular Biology (2015-10)
      The mechanisms that drive hepatocellular carcinoma (HCC) development are not well understood. Heat shock protein 70 (HSP70) plays a critical role in protein quality control. The HSP70-mediated response has been implicated in the development of different cancer types, however, the detailed mechanisms by which HSP70 supports tumor progression remains to be investigated. In this research work we observed that HSP70 deletion impairs HCC development by modulating the carcinogen-induced DNA damage response. This results in increased sensitivity to p53-dependent apoptosis, activation of MAPK/ERK negative feedback signaling pathway, and induction of cellular senescence. Inactivation of HSP70 may be a strategy to interfere with signaling pathways that drive liver cancer progression thus offering a therapeutic possibility for human HCC treatment. Note: The research data described in this Ph.D. Thesis are not published. Additional experimental work is needed to verify the data and solidify the mechanistic conclusions of this work before we seek publication of the data in a peer reviewed scientific journal. In light of new data generated from additional studies, we may need to modify or revised our mechanistic conclusions.
    • Heat Shock Protein 70I Promotes Carcinogen-induced Liver Tumorigenesis by Regulating Hepatic Metabolism and Insulin Sensitivity

      Cho, Wonkyoung; Department of Biochemistry and Molecular Biology (2011-12)
      Hepatocellular carcinoma (HCC) is one of the most lethal and prevalent cancers in the world. The treatment options for HCC, however are very limited. In mice, the carcinogen diethylnitrosamine (DEN) induces HCC, which has been proven to be comparable to human HCC in many key aspects. DEN-induced HCC leads to initial hepatocyte death followed by compensatory proliferation and inflammatory response. The cycles of hepatocyte death and compensatory proliferation eventually lead to genomic mutations and HCC development. The inducible heat shock protein-HSP70 (HSP70i) is overexpressed in a number of malignancies, including liver cancer. Tumor cells have metabolic changes which producing intermediates for cell growth and division. We hypothesize that HSP70i plays a role in HCC development through its control of glucose metabolism. To determine the impact of HSP70i in HCC, we treated a cohort of wild-type and hsp70i-deficient mice using the carcinogen DEN. Tumor development in the liver was examined after 8 months. Results show that the deletion of hsp70i leads to a significant delay in HCC development. DEN-treated hsp70i-/- mice exhibit reduced levels of alanine aminotransferase (ALT) and asparate aminotransferase (AST) in the serum compared to wild-type (WT) mice, suggesting reduced liver damage in hsp70i-/- mice. Furthermore, to investigate the mechanisms underlying HSP70i inhibition of tumorigenesis, we performed TUNEL assays to detect hepatocyte death, and Ki67 immunostaining to detect hepatocyte proliferation. As expected, hsp70i-/- mice exhibit a lower level of cell death and lower levels of cellular proliferations compared to wild-type mice. In addition, hsp70i-/- mice exhibit increased glucose consumption as evident by an increase in key enzymes involved in both glycolysis and TCA cycle. Low net glucose production induces lower lipid accumulation. Finally, treatment of DEN-treated wild-type mice with 2-phenylethynesulfonamid (PES), which is an HSP70i specific inhibitor, also delays HCC development. Overall, the alterations in the metabolic pathways in hsp70i null mice appear to contribute to delayed HCC development. Therefore, we conclude that HSP70i can be a powerful therapeutic target for HCC.
    • A Histologic Examination of the Effects of Flouride on The Gastric Mucosa of The Rat

      Easmann, Ronald; Department of Oral Biology and Diagnostic Sciences (1983-12)
      N?A
    • HMGB1-TLR4 Signaling Following Traumatic Brain Injury

      Laird, Melissa D; Department of Neurosurgery (2011-05)
      Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Although preventative measures may reduce the incidence of TBI, over 1.7 million Americans suffer a head injury annually1. Brain edema, the abnormal accumulation of fluid within the brain parenchyma, contributes to elevated intracranial pressure (ICP), brain herniation, and a poor prognosis following head injury2"4. Clinically, the degree of swelling on the first computed tomography (CT) scan directly correlates with patient outcome, demonstrating the need to limit brain edema following head injury5. Unfortunately, current medical therapies do not effectively control brain edema and neurosurgical approaches to alleviate increased ICP are invasive and of limited utility. A longrange goal of our laboratory is to elucidate the molecular and cellular mechanisms that promote cerebral edema, which may aid in the development of novel therapeutics for head trauma patients. A central premise of our hypothesis is that activation of Toll-like receptor 4 (TLR4) increases brain edema following TBI. Toll-like receptors (TLR) are membrane proteins within the interleukin-1 receptor superfamily that mediate innate immunity6"8; however, recent evidence suggests TLR are also expressed within the CNS of humans and rodents9"12. Activation of TLR4 exacerbated neuronal injury and neuroinflammation following cerebral ischemia13,14, although the involvement of TLR4 following TBI has only just begun to be examined and comparatively little is known15,16. Given the association between inflammation, neurological injury, and patient outcome17, TLR4 may represent an unexplored therapeutic target following TBI. We hypothesize that High Mobility Group Box Protein B1 (HMGB1), a putative endogenous ligand forTLR4, is released via an NR2B mechanism and promotes cellular edema following TBI.
    • HSP90 Inhibitors in Sepsis and Sepsis-induced Acute Lung Injury

      Chatterjee, Anuran; Vascular Biology Center (2007-06)
      Severe sepsis is the leading cause of death for patients in intensive care units. Patients with severe sepsis develop multiple organ failure, including acute lung injury, resulting from a dysregulated inflammatory response. Inhibitors of the ubiquitous chaperone, heat shock protein 90 (hsp90), block the activity of certain pro-inflammatory mediators, in vitro. We hypothesized that hsp90 inhibitors may ameliorate the inflammation and acute lung injury associated with severe sepsis. Male C57Bl/6 mice received either one of two hsp90 inhibitors, radicicol or 17-allylaminodemethoxygeldanamycin (17-AAG), at 24, 12, 6 and 0 hr before receiving a lethal dose of endotoxin (6.75 x 104 EU / g body weight). Outcomes included survival and parameters of systemic inflammation (plasma cytokine, chemokine and nitrite/nitrate levels), pulmonary inflammation (lung NF-κB and myeloperoxidase activities, inducible nitric oxide or iNOS expression, iNOS-hsp90 complex formation, leukocyte infiltration), and lung injury (pulmonary capillary leak, expression of endothelial specific cell-adhesion or adherens junction proteins, lung function). Mice pre-treated with vehicle and receiving endotoxin exhibited 100% 24-hr lethality, dramatic increase in all parameters of systemic and pulmonary inflammation, reduced lung function and increased capillary leak associated with reduced expression of functional adherens junction proteins. In comparison, mice receiving either radicicol or 17-AAG prior to endotoxin, exhibited prolonged survival, reduced or abolished increases in systemic and pulmonary inflammatory parameters, normal lung function and attenuated capillary leak with restored expression of adherens junction proteins. Additionally, in an in vitro model of endotoxin and activated neutrophil-induced endothelial barrier dysfunction, we show that pre-incubation of neutrophils or endothelial cells or both with hsp90 inhibitors impart a profound barrier protective effect, which is mediated, at-least in part, through reduced activation of pp60Src kinase (an hsp90 client protein) and phosphorylation of the focal adhesion protein paxillin, a pp60Src kinase substrate. Hsp90 inhibitors are drugs already in use clinically as adjunct cancer treatment. Therefore, these findings point to a potential clinical use of these drugs in sepsis and sepsis induced ALI.
    • Human Placental Na+-H+ Exchanger: Properties and Function

      Daniel, Balkovets; Department of Cell and Molecular Biology (1988-07)
    • Identification and Characterization o f CRIPlb: A Novel CBi Cannabinoid Receptor Interacting Protein

      Niehaus, Jason L.; Department of Biological Sciences (2006-07)
      G protein-coupled receptors (GPCRs) transduce extracellular stimuli to intracellular signals through their interaction with heterotrimeric G proteins. Signaling diversity and specificity is imparted primarily through variations o f G protein subunits. Protein-protein interactions between intracellular accessory proteins and GPCRs also modify signaling by altering receptor activity or signaling pathways. The ability of intracellular proteins to interact with the CBi cannabinoid receptor was investigated to determine whether particular signaling properties of CBi resulted from interaction with specific CBi interacting proteins. A novel protein named C RIPlb was discovered to interact with the C-terminal tail o f CB). The interaction between CRIPlb and CBi was characterized using the yeast two-hybrid assay. Functional consequences of the CRIPlb- CB| interaction were investigated by examining protein localization by confocal microscopy and measuring CBi mediated N-type Ca2+ channel activity in the presence of CRIPlb by whole-cell patch clamp recordings. The yeast two-hybrid assay indicated that the last nine amino acids of the CBi C-terminal tail were required for interaction with CRIPlb. Heterologous expression of C RIPlb and CBi in HEK 293 cells did not reveal evidence of colocalization, nor was CBi able to significantly traffic C RIPlb to the plasma membrane. However, CRIPlb and CBi were found to colocalize in superior cervical ganglion (SCG) neurons. Whole-cell voltage-clamp recordings of N-type Ca2+ channels in SCG neurons indicated that CRIPlb had no effect on agonist- or inverse agonist-induced modulation of Ca2+ current by CBi. Furthermore, the level of CBi constitutive activity was not significantly altered by CRIPlb. The high affinity of CBi for G proteins, as demonstrated by the ability of CBi to sequester G proteins from other Gi/0 coupled receptors, was unaffected by expression of CRIP lb. These results provide evidence that CRIPlb is a novel CBi accessory protein that interacts with the C-terminal tail of CBi. While CRIPlb and CBi can apparently interact in a neuronal expression system, the ability of CRIPlb to modify CBi signaling was not detected in any of the pathways investigated. Thus, the distinctive signaling properties of CB|, such as constitutive activity and G protein sequestration do not originate from nor are modified by CRIPlb.
    • Identification and Characterization of Two New Players in DNA Double-Strand Break Repair - PSF and p54(nrb)

      Udayakumar, Durga; Department of Molecular Medicine (2005-12)
      The stability and integrity of a genome depends on how accurately the genetic information is passed on to each daughter of a dividing cell. This accuracy is compromised when the genome is exposed to various stressful conditions, including ionizing radiation (IR), radiomimetic agents such as bleomycin, neocarzinostatin, and etoposide, free radicals generated from metabolic processes, and also errors during replication. The effect is DNA damage resulting in potentially lethal double-strand breaks (DSBs). The causes are as follows: DSBs are also created as intermediates during specialized recombination processes, such as V(D)J recombination, immunoglobulin class switching and somatic hypermutation.
    • Identification of Muscarinic Receptor Subtypes and Arachidonic Acid Metabolites Mediating the Effects of Actylcholine in The Pulmonary Circulation of Rabbits and Cats

      El-Kashef, Hassan; Department of Pharmacology (1987-05)
      Acetylch.oline (ACh) is known ·to reduce vascular pressure throughout the systemic. circulation; in. the·-- pulmonary circulatfon: ACh: can·- produce:either vasodi-1ationr or' ·vasoconstri-ction. For example,. ACh', produces: vasoconstrictfon · in· the, pulmonary ·circula~i on· of rabbits .. but dtlati on in· the· -feline. pu·lmof!ary-, vasculature·~-- The·· mechanism(s-) responsible·' for· the· actions of ACh in the pulmona.ry vasculature-- remain unc;lear. This study was designed to i·nve·st.igate poss·ible mechanisms. responsible for the actions. of ACh in the ra~bit ancf cat pulmonari_.circulation·~- Our hypothesi's is tbat . variations in· the· v.as.cular ·-response~ to: ACh may- be due to differe.nces in med-iators. (e.g. ·prostanoids)· released upon. activation .. of the muscarinic receptor~ These· di.ffe-rences cou 1 d be attributed,· either to. differences ... in muscarinic receptor subtypes.-. or to differences. in the·. metabolism of· arachidonic acid- tn rabbit. vs. cat. In anesthetized rabbits,_ ACh-induced pulmonary=- vasoconstriction-··. was,. totatly, inhibited::'·- by:: the: phosphotipasey A'2· inhibitor· qu-inacrine··,. the cycl o~oxygenase"' inhibitors:; indomethacin·,. and,.~ mec lofenamate·,, the- thtomboxane/ A:2:· synthetase=, i nh~i bi:tot· ]-;.;.{1'- Imidazolyl.)-· Heptano.fc. Acid .. (7;..IHA), and'- by,- the··' thromboxane·· A- 2 . receptor·· antagpntst. SQ:. 29-~.548:, .. but not·,. by·- the· 1 .ipoxygenase:-- inhibitor- nordihydrogua-iaret.ic: acid( NDGA}':. AGh·: s:igni-ftcantly; increased> plasma; thromboxane···B2.' (TXB'2J:· levels;. in·-. anesthetized:·,_ rabb_its:. A.Ch:~induced:. decrease'~ in, system.ic ar.teria:l pressure'" was, not· affected: by:·. any o.f'· the·· i nh'ibftors,. mentionedJ above--._ Small>. doses: of· the, select.i ve:· Mi- muscari nfc. receptor· subtype· antagonists:, pi renzepihe and_:. tr.ihexypheni:d~l,.. s:i gni-f.i cantly:- fnhi bjted:-: the· ACh.-i nduced:~- increase:'-·. i m pulmonary; vascuJa·r res:fstance- but. not: the~ ACh-induced=;· decrease Ht systemic. arterfal~: pressur.e··. The:.- s·ame" dose·· o.f secover.i ne:, .. a-~.- se·l ecti ve, M2-- muscar.i.nic: ii recept.or subtype. antagonist, dld ·not· change the · ACh ·effects on the pu 1 mona ry or· sys.temi c · v qSCu latu,re. Larger doses of pirenzepine, trihexyphen-idyl and\· secoverine,· totally. inhibited· the.- effects:: of ACh in· the .. pu:lmonary· and: systemic: circulatjons. Atrop.ine··. equally:- inh.i.bi ted:· the· effects. of ACn· on'" the pulmonary..- and.: systemic vascul atures- at.- any. do$es~ . . used': In .. fso_lated· rabbit·. lungs .. perfused·:·in:· situ~: w:ith · b]ood·-,_'free· medium;< . . . . . . . the ACh-fnduced· increases fn .. ·pulmonary v.ascular resistance, TXB2 level·s: a:nd ·6-Keto~PG·Fra were significa.nt.ly inhibited. by small concentrations.· of· pi.renzepine but .not· secove·rine. Larger concentrations. of· p.irenzepine~ and:'· · . . secover·ine totally ·inhibited· these· effects of ACh. In -anesthetized c~ts, the· ACh~inducec:l decre-ase in pulmonary vascular resfstance was partially~ · inhibited· by quinacrine and·' indomethacin and· significantly:· .potenti~ted by NOGA. The ACh-induced ·decrease in systemic arterial .pressure was not s·ignificantly affected by· any. of these· inhibitors. Small. doses. of secover-ine:'' but not . pfrenzepi ne;~" i nh.ibited·· the: pulmonary: but,. not .. the:· systemic vascular-. response·, tct.. ACh.,,_ i!!.=- v:ivo~ Howev-er,_. large··· doses; .. of·.· ptrenz:epi ne-, · tri·hexyphen:fdyl. and' s.ecoveri'ne' significantly:· inh.i bited~ the:, .. . . effects. of:. ACh~ in·.: the~: pulmonary;· and. systemic vascu:l ature\ In: isola ted:· cat: 1 ung_s:. perfused~- fm: sitw: w.ith; bJ ood.;.free- · medium~. 'ACh'" di-lated... the·· precons.tricted:: pulmonary: artery. bu.t> tt: did·: not ·s,tgnific.antly:· alter- TXB2 ori 6~ Keto~PGF 1 at 1 eveTs:~.. Smal:T: concentrat:i ons:- of:-· secoverfne-': but· not· pJ.renzep.i ne~-- par.t.ially;' i nhi bi'tedr the· ACh;.. induced~· decrease· in: pulinonar,Yvascular ·· resistance· •. The· pros.tacyc;ti n .. · synthetase fnhi bitor· tranylcypromine· si"gn.f$icantly~ i'nhi bited;'; the,· ACh- induced§ decrease:· in:· · pu]monary.:; va-scu..lar· resi.stance·~- . . i fi: ·These· results. ·indi-cate that l) ACh has . opposite actions in. the systemic {dilatory) versus pulmonary· (constrictor) circulation of rabbi-ts, 2r Arachidon-ic· acid.'metabo'lftes·. mediate. the-. pulmonary: . but. :not·· .the" systemic vascular respon.se- to. ACh, in rabbit, 3}. Thromboxane·· A2 mediates,. the:· pulmonary- vasoconstrictor- response·· to, ACh in rabbit·~ 4} The r.abbit pulmonary . v~scular· muscarinic recepto.rs. are· very·,· sensit:ive to·. p_irenzep.i-ne· . and thus be:have m9re · 1 ike Mi recept~rs, _5) · In· the cat·, the· ACh- induced·· decrease in- p~lmonary but not systemic vascular. pressure is partly mediated by prostacycli'n, 6)' In _the cat, the vascula-r· muscarinic receptors both in the· pulmon~ry. and the systemic beds are not selectively sensitive to . .pirenz.ep.ine ·and- thus behave like. non-Mt receptors and,· 7) In the .cat, the· ·muscarinic receptors. in the· pulmonary. and, systemic vasculat~re· represent different or heterogenous populations of M2. receptors since· they exhibit different affinities·. to secoverine.
    • Identification of professional competencies needed for practicing registered nurses in urban and rural hospitals

      Isler, Barbara A.; School of Nursing (1981-05)
      The purpose of this study was to determine if the hospital- location .s i gni fi cantly influenced the regis ter.ed nurses• competency needs .. A. sample of 112 urban and 80 rural .nurses was selected by Nursing Directors in 23 Georgia hospitals. Data were collected by use of a 113 item . competency questionnaire adapted from Clayton'·s (1978) work in thi.s area .. · Findings suggest the urban o~ rural hospital setting significantly . influences the competencies used by the registered nurse. Other findings include the acceptance percentage for ea-ch competency by the urban or. rural nurse indicating thei~ perception of nee~ and demographic characteristics of the two nurse populations.
    • Identification of RAB11-Family Interacting Proteins (RAB11-F1Ps): Integral Components in Plasma Membrane Recycling

      Hales, Chadwick M; Institute of Molecular Medicine and Genetics (2003-05)
      Given the involvement of Rabl la in each of these cellular processes and given the potential impact of Rabl la on human health and disease, we sought to further establish a role for Rabl la in plasma membrane recycling. Since other Rab proteins have numerous characterized interacting proteins and because the repetoire for Rabl la is currently limited to three identified interacting proteins, we hypothesized that other Rabl la binding partners exist as putative downstream effectors for the small GTPase. We therefore proposed the following three aims: Aim 1: Identify R ab lla interacting proteins. Aim 2: Determine the effect of interacting proteins on membrane recycling. Aim 3: Establish an organizational model of a putative Rabl la complex. The progression of studies herein provides insight into the dynamic and complex process of plasma membrane recycling. Yeast two hybrid screening of a parietal cell cDNA library utilizing dominant active Rabl laS20V as the bait identified Rabl 1-Family Interacting Protein 1 (Rabll-FIPl), a novel R ab lla interacting protein. EST database searches with the R abll-FIPl sequence identified three homologous proteins with high carboxyl-terminal identity. Chapter 1 introduces the new family of Rabl la interacting proteins and provides the initial characterization. Interestingly, these studies indicated an interaction between Rabll-Family Interacting Protein 2 (Rabll-FIP2) and myosin Vb tail. Chapter 2 further describes the Rabl l-FIP2/myosin Vb tail binding and provides functional data placing Rabll-FIP2 as an integral component of the plasma membrane recycling system. Finally, recent studies have indicated a recycling system dependence on different kinase activities. Through kinase inhibitor studies and immunofluorescence imaging, evidence presented in Chapter 3 suggests that R ab lla along with multiple Rabll-FIP proteins function as a complex beginning at the process of endocytosis with movement dependent on multiple phosphorylation events. The ultimate goal throughout these studies is to provide a clearer picture of Rabl la function in plasma membrane recycling so that one day a positive impact on human health can be achieved.
    • Identification of Regulatory Elements in a Conserved Upstream Region of the Gene Encoding Interphotoreceptor Retinoid-Binding Protein (IRBP)

      Lu, Haiyan; Department of Ophthalmology (1999-06)
      (First Paragraph) IRBP is a large, single-subunit extracellular glycolipoprotein found in the interphotoreceptor matrix between the photoreceptor cells and retinal pigment epithelium cell layer (Fig. 1.). The protein is synthesized and secreted by the photoreceptor rods and cones, as well as pinealocytes, of all vertebrates. The molecular weight of human IRBP (1230 residues) is 133,400 daltons. This protein consists of four homologous segments of approximately 300 residues each. Each segment contains highly conserved hydrophobic domains among species. Ligands identified as bound to IRBP include retinoid isomers and fatty acids, and IRBP can also bind cholesterol, a-tocopherol and retinoic acid. The ability of IRBP to bind various retinoid isomers, fatty acids and many other hydrophobic ligands suggests multiple functions in the retina .
    • The Identification of the Requisite Knowledge and Relevant Role Activities by Nurse Administrators and the Relationship of These to Their Educational Preparation and Management Level

      Allen, Lori; Department of Nursing (1988-01)
      The purpose.of this descriptive correlational study was to identify the requisite knowledge and relevant role activities needed by nurse administrators to successfully enact their roles (first, mid, and top) and the relationship of these role knowledge areas and role.activities to their educational preparation and management level. To achieve the study purpose, two research questions and three hypotheses were tested. A total of 226 subjects participated in the study: 156 first-line nurse administrators; 44 mid level administrators.; and 26 top level nurse administrators. The study population consisted of a convenience sample of nurse administrators from five hospitals in a Southeastern metropolitan area. Data were collected through the use of the Nurse Administrative Role Aetivities ·and Knowledge (NARAA~) tool. Descriptive statistics were utilized to address the first research question. To test the hypptheses related to the second research question, ANOVA were utilized-. All three hypotheses were supported at the p=.05 level. More specifically, 13 role activities and four requisiteknowlege areas were found to be significantly different for first level .. and .top level administrators. The majority of these items were related to leadership, management, and administration of human resources. Seven role activities and 11 requisite knowledge areas were found to differ on the basis of educational preparation. Nurse administrators at each organizational level identified significantly different role activities·relevant for.their successful role enactment, but did not identify different requisite role knowledge areas. There was no significant difference in how nurses with different academic degrees rated the relevance of role activities to the success of their role enactment on the basis of academic degree. Academic degree did, however, discriminate among respondents in the degree to which they rated the relevance of requisite knowledge areas to the success of their role enactment. Other findings, limitations, implications, and suggestions for further study were discussed.
    • Immune regulation of tumor cell plasticity: A promising molecular target in breast cancer metastasis

      LEE, EUNMI; Department of Biochemistry and Molecular Biology / Cancer Center (2018-11-29)
      It is widely accepted that phenotypic plasticity of malignant cells is required during metastatic cascade. However, the specific mechanism of how the tumor microenvironment regulates tumor cell plasticity in metastasis is under intense investigation. We demonstrate here that monocytic and granulocytic subsets of myeloid-derived suppressor cells (MDSC), hereafter called mMDSCs and gMDSCs, infiltrate in the primary tumor and distant organs with different time kinetics and regulate spatiotemporal tumor plasticity. Using co-culture experiments and mouse transcriptome analyses in syngeneic mouse models, we provide evidence that tumor-infiltrating mMDSCs facilitate dissemination from the primary site by inducing the EMT/CSC phenotype. In contrast, pulmonary gMDSC infiltrates support metastatic growth by reverting the EMT/CSC phenotype and promoting tumor cell proliferation. We also observe that lung-derived gMDSCs isolated from tumor-bearing mice enhance metastatic growth of already disseminated tumor cells. Our ongoing studies reveal that calprotectin (S100A8 and S100A9 heterotetramer) is an important regulator of gMDSCs, which play a critical role in promoting breast cancer metastasis by inducing MET-like CSCs as well as suppressing anti-tumor immunity within the pre-metastatic niche. Furthermore, we develop a novel gMDSC-targeting compound that potentially binds to calprotectin and validate its therapeutic utility in a preclinical breast cancer model. Our goal for this study is to elucidate the molecular co-evolution of tumor and immune cells in cancer development and to identify molecular targets to provide alternative therapeutic options for women with metastatic disease.