Adhesion Mechanisms Mediating Sickle Cell Vasooclusion In Vivo

Summary

Principal Investigator: Paul S Frenette
Abstract: DESCRIPTION (provided by applicant): Under this project, we have previously found using intravital microcopy imaging in a humanized mouse model of sickle cell disease (SCD) that adherent leukocytes recruited in inflamed venules, played a direct role in VOC by interacting with circulating erythrocytes (RBC). We have determined that RBCs interact specifically with adherent polymorphonuclear neutrophils (PMNs) in vivo. We have identified E-selectin ligand-1 as a major adhesion receptor sending signals that contribute to activate the beta2 integrin Mac-1 specifically at the leading edge of crawling PMNs. Neutrophil Mac-1 captures circulating RBC and thus contribute to VOC. Our preliminary studies suggest that VOC is mediated by a subset of PMNs (senescent phenotype) which we propose to characterize. Other exciting preliminary studies suggest that neural signals regulate the expression of adhesion molecules on venular endothelial cells through circadian adrenergic signals and that these signals can modulate the inflammatory response and the clearance of senescent PMNs. In Specific Aim 1, we will test whether senescent PMNs promote heterotypic interactions and acute VOC in SCD. We will dissect the contribution of PMN aging vs. activation on their ability to promote in vivo heterotypi RBC-WBC interactions following ex vivo aging and stimulation. We will evaluate gain- and loss-of function model systems that promote or reduce senescent PMN clearance in the bone marrow or survival in the circulation. Preliminary data indicate that circadian adrenergic signals are locally delivered by nerves of the sympathetic nervous system (SNS). However, SNS nerves innervate arterioles, but not venules where leukocytes are recruited, raising the intriguing question as to how these signals are transmitted to venular endothelial cells. In Specific Aim 2, we will define how SNS nerves control endothelial cell function in venules. We will track in vivo signal transduction by imaging calcium waves using GCaMP3 mice following direct neural stimulation of the genitofemoral nerve or pericytes by micropipette stimulation in collaboration with Dr. David Spray (Einstein). We will identify genetically the cellular and molecular basis by specific deletion of connexins or beta2 adrenergic receptors (Adrb2fl/fl) in pericytes or endothelial cells, and we will investigate the functional consequences of tissue-specific deletions on circadian leukocyte recruitment in healthy wild-type mice and in SCD mice. In addition to the SNS, our preliminary data also suggest a role for parasympathetic nervous system (PNS) in leukocyte recruitment. We will investigate in Specific Aim 3 the role of PNS (cholinergic) signals in leukocyte adhesion and sickle cell vaso-occlusion. We will explore in collaboration with Dr. Kevin Tracey (Feinstein Institute for Medical Research), the influence of vagal stimulation and nicotinic receptor signaling. We will also evaluate the role of the type 1 muscarinic receptor (Chrm1) using pharmacologic and genetic analyses since our preliminary studies suggest a role for this receptor in leukocyte trafficking. These studies will provide new insight on the mechanisms regulating sickle cell VOC and lead to novel ways to target inflammation.
Funding Period: 2001-09-30 - 2017-06-30
more information: NIH RePORT

Top Publications

  1. ncbi Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow
    Yoshio Katayama
    Department of Medicine, Immunobiology Center and Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, NY 10029, USA
    Cell 124:407-21. 2006
  2. pmc GM-CSF controls nonlymphoid tissue dendritic cell homeostasis but is dispensable for the differentiation of inflammatory dendritic cells
    Melanie Greter
    Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA
    Immunity 36:1031-46. 2012
  3. pmc Deciphering the transcriptional network of the dendritic cell lineage
    Jennifer C Miller
    Immunology Institute, Mount Sinai School of Medicine, New York, New York, USA
    Nat Immunol 13:888-99. 2012
  4. pmc Hydroxyurea and a cGMP-amplifying agent have immediate benefits on acute vaso-occlusive events in sickle cell disease mice
    Camila Bononi Almeida
    Hematology and Hemotherapy Center, Instituto Nacional de Ciência e Tecnologia do Sangue INCTS, UNICAMP, Campinas, Sao Paulo, Brazil
    Blood 120:2879-88. 2012
  5. pmc Adrenergic nerves govern circadian leukocyte recruitment to tissues
    Christoph Scheiermann
    Ruth L and David S Gottesman Institute for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, New York, NY 10461, USA
    Immunity 37:290-301. 2012
  6. pmc The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine
    Paolo Bianco
    Department of Molecular Medicine, La Sapienza Universita di Roma, Rome, Italy
    Nat Med 19:35-42. 2013
  7. ncbi Mesenchymal stem cell: keystone of the hematopoietic stem cell niche and a stepping-stone for regenerative medicine
    Paul S Frenette
    Ruth L and David S Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York 10461, USA
    Annu Rev Immunol 31:285-316. 2013
  8. pmc Circadian control of the immune system
    Christoph Scheiermann
    Ruth L and David S Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York 10461, USA
    Nat Rev Immunol 13:190-8. 2013
  9. pmc CD169⁺ macrophages provide a niche promoting erythropoiesis under homeostasis and stress
    Andrew Chow
    Ruth L and David S Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York, USA
    Nat Med 19:429-36. 2013
  10. pmc This niche is a maze; an amazing niche
    Maher Hanoun
    Ruth L and David S Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA
    Cell Stem Cell 12:391-2. 2013

Detail Information

Publications33

  1. ncbi Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow
    Yoshio Katayama
    Department of Medicine, Immunobiology Center and Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, NY 10029, USA
    Cell 124:407-21. 2006
    ..Further, administration of a beta(2) adrenergic agonist enhances mobilization in both control and NE-deficient mice. Thus, these results indicate that the sympathetic nervous system regulates the attraction of stem cells to their niche...
  2. pmc GM-CSF controls nonlymphoid tissue dendritic cell homeostasis but is dispensable for the differentiation of inflammatory dendritic cells
    Melanie Greter
    Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA
    Immunity 36:1031-46. 2012
    ..Thus, Csf-2 is important in vaccine-induced CD8(+) T cell immunity through the regulation of nonlymphoid tissue DC homeostasis rather than control of inflammatory DCs in vivo...
  3. pmc Deciphering the transcriptional network of the dendritic cell lineage
    Jennifer C Miller
    Immunology Institute, Mount Sinai School of Medicine, New York, New York, USA
    Nat Immunol 13:888-99. 2012
    ..We also identified a transcriptional program expressed specifically during the steady-state migration of tissue DCs to the draining lymph nodes that may control tolerance to self tissue antigens...
  4. pmc Hydroxyurea and a cGMP-amplifying agent have immediate benefits on acute vaso-occlusive events in sickle cell disease mice
    Camila Bononi Almeida
    Hematology and Hemotherapy Center, Instituto Nacional de Ciência e Tecnologia do Sangue INCTS, UNICAMP, Campinas, Sao Paulo, Brazil
    Blood 120:2879-88. 2012
    ..In addition, inhibition of PDE9, an enzyme highly expressed in hematopoietic cells, amplified the cGMP-elevating effects of hydroxyurea and may represent a promising and more tissue-specific adjuvant therapy for this disease...
  5. pmc Adrenergic nerves govern circadian leukocyte recruitment to tissues
    Christoph Scheiermann
    Ruth L and David S Gottesman Institute for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, New York, NY 10461, USA
    Immunity 37:290-301. 2012
    ..These data provide unique insights in the leukocyte adhesion cascade and the potential for time-based therapeutics for transplantation and inflammatory diseases...
  6. pmc The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine
    Paolo Bianco
    Department of Molecular Medicine, La Sapienza Universita di Roma, Rome, Italy
    Nat Med 19:35-42. 2013
    ..These uncertainties have a major impact on their envisioned therapeutic use...
  7. ncbi Mesenchymal stem cell: keystone of the hematopoietic stem cell niche and a stepping-stone for regenerative medicine
    Paul S Frenette
    Ruth L and David S Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York 10461, USA
    Annu Rev Immunol 31:285-316. 2013
    ..We review their role and that of other putative niche constituents in the regulation of bone marrow HSCs. Additionally, how MSCs and their stromal progeny alter immune function is discussed, as well as potential therapeutic implications...
  8. pmc Circadian control of the immune system
    Christoph Scheiermann
    Ruth L and David S Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York 10461, USA
    Nat Rev Immunol 13:190-8. 2013
    ..This Review summarizes the current knowledge of circadian rhythms in the immune system and provides an outlook on potential future implications...
  9. pmc CD169⁺ macrophages provide a niche promoting erythropoiesis under homeostasis and stress
    Andrew Chow
    Ruth L and David S Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York, USA
    Nat Med 19:429-36. 2013
    ..These results indicate that CD169(+) macrophages promote late erythroid maturation and that modulation of the macrophage compartment may be a new strategy to treat erythropoietic disorders...
  10. pmc This niche is a maze; an amazing niche
    Maher Hanoun
    Ruth L and David S Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA
    Cell Stem Cell 12:391-2. 2013
    ..Two recent studies in Nature (Ding and Morrison, 2013; Greenbaum et al., 2013) have shed light into the bone marrow stromal subsets making CXCL12, a chemokine critical for HSC maintenance...
  11. pmc Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes
    Daigo Hashimoto
    Department of Oncological Sciences and Tisch Cancer Institute, Critical Care and Sleep Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA
    Immunity 38:792-804. 2013
    ..Collectively, these results indicate that tissue-resident macrophages and circulating monocytes should be classified as mononuclear phagocyte lineages that are independently maintained in the steady state...
  12. pmc Chemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration
    Daniel Lucas
    Ruth L and David S Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, New York, New York, USA
    Nat Med 19:695-703. 2013
    ..These results demonstrate the potential benefit of adrenergic nerve protection for shielding hematopoietic niches from injury...
  13. ncbi Autonomic nerve development contributes to prostate cancer progression
    Claire Magnon
    Ruth L and David S Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA
    Science 341:1236361. 2013
    ..These findings may lead to novel therapeutic approaches for prostate cancer. ..
  14. pmc Arteriolar niches maintain haematopoietic stem cell quiescence
    Yuya Kunisaki
    1 Ruth L and David S Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York 10461, USA 2 Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA
    Nature 502:637-43. 2013
    ..Conditional depletion of NG2(+) cells induces HSC cycling and reduces functional long-term repopulating HSCs in the bone marrow. These results thus indicate that arteriolar niches are indispensable for maintaining HSC quiescence. ..
  15. pmc Vasculature-associated cells expressing nestin in developing bones encompass early cells in the osteoblast and endothelial lineage
    Noriaki Ono
    Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
    Dev Cell 29:330-9. 2014
    ..These findings reveal an emerging complexity of stromal populations, accommodating Nes(+) cells as vasculature-associated early cells in the osteoblast and endothelial lineage. ..
  16. pmc Intravenous immunoglobulins modulate neutrophil activation and vascular injury through FcγRIII and SHP-1
    Jung Eun Jang
    Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA
    Circ Res 110:1057-66. 2012
    ..Intravenous immunoglobulin (IVIG) has been shown to have a beneficial effect in systemic inflammatory disorders; however, the mechanisms underlying IVIG's inhibitory effect on neutrophil recruitment and activation are not understood...
  17. pmc Pretransplant CSF-1 therapy expands recipient macrophages and ameliorates GVHD after allogeneic hematopoietic cell transplantation
    Daigo Hashimoto
    Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA
    J Exp Med 208:1069-82. 2011
    ..This study establishes the unexpected key role of host macrophages in inhibiting GVHD and identifies CSF-1 as a potential prophylactic therapy to limit acute GVHD after allo-HCT in the clinic...
  18. pmc Physiological contribution of CD44 as a ligand for E-Selectin during inflammatory T-cell recruitment
    Maria Nacher
    Department of Epidemiology, Atherothrombosis and Imaging, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
    Am J Pathol 178:2437-46. 2011
    ..Our results identify additional mechanisms by which CD44 modulates the inflammatory response...
  19. pmc Identification of a radio-resistant and cycling dermal dendritic cell population in mice and men
    Milena Bogunovic
    Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA
    J Exp Med 203:2627-38. 2006
    ..Given the role of residual host tissue DCs in transplant immune reactions, these results suggest that dermal DC homeostasis may contribute to the development of cutaneous graft-versus-host disease in clinical transplantation...
  20. ncbi Imaging receptor microdomains on leukocyte subsets in live mice
    Elaine Y Chiang
    Department of Medicine and Immunobiology Center, Mount Sinai School of Medicine, One Gustave L Levy Place, New York, New York 10029, USA
    Nat Methods 4:219-22. 2007
    ..Most adherent Gr-1+ leukocytes are not firmly stationary but actively migrate on TNF-alpha-activated cremasteric venular endothelium and exhibit marked polarization of surface PSGL-1, but not LFA-1, to the trailing edge...
  21. pmc Sickle cell disease: old discoveries, new concepts, and future promise
    Paul S Frenette
    Division of Hematology Oncology, Mount Sinai School of Medicine, New York, New York 10029, USA
    J Clin Invest 117:850-8. 2007
    ..In this review, we discuss some of the important advances in this field and the impediments that limit the impact of these advances...
  22. pmc Complete identification of E-selectin ligands on neutrophils reveals distinct functions of PSGL-1, ESL-1, and CD44
    Andres Hidalgo
    Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA
    Immunity 26:477-89. 2007
    ..These results suggest distinct and dynamic contributions of these three glycoproteins in selectin-mediated neutrophil adhesion and signaling...
  23. pmc Intravenous immunoglobulins reverse acute vaso-occlusive crises in sickle cell mice through rapid inhibition of neutrophil adhesion
    Jungshan Chang
    Mount Sinai School of Medicine, Department of Medicine, Immunobiology Center and Black Family Stem Cell Institute, New York, NY 10029, USA
    Blood 111:915-23. 2008
    ..These data suggest that the potential therapeutic benefits of IVIG in SCD crises should be evaluated in a clinical trial...
  24. ncbi Hematopoietic stem cell trafficking: regulated adhesion and attraction to bone marrow microenvironment
    Simon Mendez-Ferrer
    Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA
    Ann N Y Acad Sci 1116:392-413. 2007
    ..Recent studies suggest that G-CSF-mediated suppression requires signals from the sympathetic nervous system (SNS). This review summarizes emerging concepts thought to contribute to stem cell migration...
  25. pmc The vessel wall and its interactions
    Denisa D Wagner
    Immune Disease Institute and Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
    Blood 111:5271-81. 2008
    ..In this review, we relate the history of blood cell interactions with the vasculature, discuss recent progress, and raise some unresolved questions awaiting the field...
  26. pmc Heterotypic interactions enabled by polarized neutrophil microdomains mediate thromboinflammatory injury
    Andres Hidalgo
    Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA
    Nat Med 15:384-91. 2009
    ..These results indicate that endothelial selectins can influence neutrophil behavior beyond its canonical rolling step through delayed, organ-damaging, polarized activation...
  27. pmc Circadian rhythms influence hematopoietic stem cells
    Simon Mendez-Ferrer
    Department of Medicine, USA bDepartment of Gene and Cell Medicine, USA
    Curr Opin Hematol 16:235-42. 2009
    ..There is increasing evidence showing the impact of biological rhythms on the traffic of hematopoietic stem cells (HSCs) and their proliferation and differentiation capacities...
  28. pmc Neutrophil microdomains: linking heterocellular interactions with vascular injury
    Christoph Scheiermann
    Department of Medicine, Tisch Cancer Institute, Mount Sinai School of Medicine, New York, New York 10029, USA
    Curr Opin Hematol 17:25-30. 2010
    ..This review discusses recent advances in elucidating these neutrophil domains and their associated functions in cell adhesion...
  29. pmc Cooperation of beta(2)- and beta(3)-adrenergic receptors in hematopoietic progenitor cell mobilization
    Simon Mendez-Ferrer
    Medicine, Tisch Cancer Institute, Mount Sinai School of Medicine, New York, New York, USA
    Ann N Y Acad Sci 1192:139-44. 2010
    ..Double deficiency in beta(2)- and beta(3)-ARs compromises enforced mobilization. Therefore, beta(2)- and beta(3)-ARs have specific roles in stromal cells and cooperate during progenitor mobilization...
  30. pmc GMI-1070, a novel pan-selectin antagonist, reverses acute vascular occlusions in sickle cell mice
    Jungshan Chang
    Departments of Medicine and Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY, USA
    Blood 116:1779-86. 2010
    ..These results suggest that GMI-1070 may represent a valuable novel therapeutic intervention for acute sickle cell crises that should be further evaluated in a clinical trial...
  31. pmc Mesenchymal and haematopoietic stem cells form a unique bone marrow niche
    Simon Mendez-Ferrer
    Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA
    Nature 466:829-34. 2010
    ..These results uncover an unprecedented partnership between two distinct somatic stem-cell types and are indicative of a unique niche in the bone marrow made of heterotypic stem-cell pairs...
  32. pmc CXCL1 and its receptor, CXCR2, mediate murine sickle cell vaso-occlusion during hemolytic transfusion reactions
    Jung Eun Jang
    Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA
    J Clin Invest 121:1397-401. 2011
    ..These results indicate that CXCL1 is a key inflammatory mediator of acute VOC in SCD mice. Targeted inhibition of CXCL1 and/or CXCR2 may therefore represent a new therapeutic approach for acute VOC in SCD patients...
  33. pmc Osterix marks distinct waves of primitive and definitive stromal progenitors during bone marrow development
    Toshihide Mizoguchi
    Ruth L and David S Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA Institute for Oral Science, Matsumoto Dental University, Shiojiri, Nagano 399 0781, Japan
    Dev Cell 29:340-9. 2014
    ..These results uncover a broad expression profile of Osterix and raise the intriguing possibility that distinct waves of stromal cells, primitive and definitive, may organize the developing BM. ..

Research Grants62

  1. Structure-function based development of JC virion specific antagonists for PML
    Walter Atwood; Fiscal Year: 2013
    ..The three major investigators on the team have built a strong working collaboration that is evidenced by the solid preliminary data supporting this application. ..
  2. Translational Analyses of Chronic Aberrant Behavior Across the Life Span
    ISER DELEON; Fiscal Year: 2013
    ..Evidence arising from this multi-site, multi-faceted approach to the treatment of CAB in IDD will make it possible to design better therapeutic individuals with IDD to lead better lives. ..
  3. Endothelial Cell Phenotypes in Health and Disease
    William C Aird; Fiscal Year: 2013
    ..Core C ("Gene Targeting Core";William C. Aird, Core Leader) provides the necessary tools for targeting the Hprt locus and the loci of endogenous genes in ES cells and mice. ..
  4. Neuro-Circulatory Function in Chronic Heart Failure
    Irving H Zucker; Fiscal Year: 2013
    ..The role of exercise training in modulating ROS generation and antioxidant enzymes in animals with CHF will also be investigated in this project. ..
  5. Shaping Antiviral Immunity by the Inflammatory, Regulatory and Tissue Environment
    E John Wherry; Fiscal Year: 2013
    ..Our goal is to define how unrelated infections impact immunological memory in hopes to improve vaccines. ..
  6. Biology and Therapy of High Risk Neuroblastoma
    ROBERT CHARLES SEEGER; Fiscal Year: 2013
    ..nant.org), which includes 15 pediatric oncology institutions across the US and in Canada. ..
  7. The role of plasmacytoid dendritic cells in corneal immunity
    Pedram Hamrah; Fiscal Year: 2013
    ..HSK is a leading cause of blindness. Effective therapy for HSK would significantly reduce visual impairment, increase productivity, and reduce the burden of treating HSK. ..
  8. Brain region dependent trafficking of myeloid precursor cells in repeated defeat.
    John F Sheridan; Fiscal Year: 2013
    ....
  9. The Conte Center for Schizophrenia Research
    Daniel C Javitt; Fiscal Year: 2013
    ..The overall goal of the Center is to develop new assessment and intervention approaches for schizophrenia based upon glutamatergic models. ..
  10. Functional Genetics of COPD
    Edwin K Silverman; Fiscal Year: 2013
    ..resistant Inbred strains which are tested with long-term cigarette smoke exposure. We anticipate that these studies will provide insight into the pathways and mechanisms for COPD susceptibility...
  11. Molecular and Force Dynamics: Leukocyte Adhesion Molecules
    SCOTT IRWIN SIMON; Fiscal Year: 2013
    ....
  12. The Role of Lymphangiogenesis in IBD Pathogenesis
    Claudio Fiocchi; Fiscal Year: 2013
    ....
  13. Role Of p120 Catenin In Sepsis-Induced Lung Injury
    Guochang Hu; Fiscal Year: 2013
    ..The identification of p120-catenin-activated pathways modulating LPS-induced sepsis will be of great interest in the design of therapeutic strategies for the treatment or prevention of acute lung injury. ..
  14. INNATE IMMUNE RESPONSE TO MICROBIAL INFECTION
    William M Nauseef; Fiscal Year: 2013
    ....
  15. DEVELOPMENTAL BIOLOGY OF HUMAN ERYTHROPOIESIS
    Stuart H Orkin; Fiscal Year: 2013
    ..abstract_text> ..
  16. Lentiviral Gene Therapy for Sickle Cell Disease and Immunodeficiency Disorders
    Brian P Sorrentino; Fiscal Year: 2013
    ..abstract_text> ..
  17. Interplay of B cells and HIV Leading to Broad Neutralizing Antibody Responses
    Pascal Poignard; Fiscal Year: 2013
    ..abstract_text> ..
  18. Systems Biology of Glycosylation
    Sriram Neelamegham; Fiscal Year: 2013
    ..v) Validation in animal models of inflammation, peritonitis and COPD (chronic obstructive pulmonary disease), key hypothesis generated using computer simulation and ex vivo experimentation. ..
  19. Regulation of Innate Immunity by the Sympathetic Nervous System Druing Sepsis
    Eric J Seeley; Fiscal Year: 2013
    ..Lastly, these studies may shed light on how chronic physiologic or psychologic stress alter susceptibility to infection. ..
  20. TARGETING THE MARCKS-FAMILY PROTEINS TO INHIBIT NEUTROPHIL MIGRATION
    Mary K Sheats; Fiscal Year: 2013
    ....
  21. CHEMISTRY AND BIOLOGY OF HEPARAN SULFATE
    UMESH RAMANLAL DESAI; Fiscal Year: 2013
    ..End of Abstract) ..
  22. Hyaluronan Matrices in Vascular Pathologies
    Vincent C Hascall; Fiscal Year: 2013
    ..abstract_text> ..
  23. PATHOPHYSIOLOGY OF THE ENDOTHELIUM
    Francis W Luscinskas; Fiscal Year: 2013
    ..g., heart attacks and strokes), as well as other organs and tissues of the body. These mechanistic insights may help identify novel therapeutic targets for the treatment of a broad spectrum of inflammatory diseases. ..
  24. HORMONAL REGULATION OF BLOOD PRESSURE
    Michal Laniado Schwartzman; Fiscal Year: 2013
    ..ular tone, in the pathophysiology of hypertension and cardiovascular disease. ..
  25. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
    ..The insights gained from the data generated from these studies will provide novel molecular targets for the development of new therapeutic strategies to treat patients with lung injury. ..
  26. LIPID AND LIPOPROTEIN METABOLISM IN ATHEROSCLEROSIS
    Alan M Fogelman; Fiscal Year: 2013
    ..These six Projects will be supported by four cores and together will form a highly interactive and synergistic Program Project that is focused on lipid and lipoprotein metabolism in atherosclerosis. ..
  27. Disruption of Autonomic Pathways in the Left Atrium by Inhibition of G-proteins
    Rishi Arora; Fiscal Year: 2013
    ..However, currently available treatment options for AF are not very effective. We propose a new method to treat AF, by using a novel peptide (protein) to inhibit the function of the nerves that trigger this arrhythmia. ..
  28. Intestinal Lymphocyte Trafficking
    Eugene C Butcher; Fiscal Year: 2013
    ....
  29. Pacific NorthWest Regional Center of Excellence (PNWRCE)
    Jay A Nelson; Fiscal Year: 2013
    ..pseudomallei host pathogen response during both the septicemic as well as the intracellular phases of the disease. ..
  30. Modulation of erythrocyte function by complement
    IONITA CALIN GHIRAN; Fiscal Year: 2013
    ....
  31. Mechanisms of State Switching in Sleep and Sleep Apnea
    Clifford B Saper; Fiscal Year: 2013
    ..This work will help to design interventions for improving the health of patients with OSA. ..
  32. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
    ..abstract_text> ..
  33. Monocyte activation and the role of CD11c in obesity-linked metabolic syndrome
    Huaizhu Wu; Fiscal Year: 2013
    ..This study has the potential to provide novel preventive and therapeutic targets for obesity-related atherosclerosis and diabetes. ..
  34. AMPK Endothelial Cell Dysfunction and the Metabolic Syndrome (PROGRAM PROJECT)
    Neil B Ruderman; Fiscal Year: 2013
    ..The proposed studies should both yield novel insights into the biological bases for the premature atherosclerosis and impaired angiogenesis associated with this entity and suggest new therapeutic targets for their prevention...
  35. MBSR Symptom Cluster Trial for Breast Cancer Survivors
    Cecile A Lengacher; Fiscal Year: 2013
    ..If this intervention is shown to be efficacious, the possibility exists of extending its use to minimize morbidity for other types of cancers, as well as severe non-cancer health disorders. ..
  36. Role of RBC NO and ATP in Sickle Vasculopathy
    Marilyn J Telen; Fiscal Year: 2013
    ..This work will allow development of new therapeutic approaches to prevent and control vaso-occlusion and tissue damage in SCD. ..
  37. ADAM-mediated Shedding in Endothelial Inflammatory Responses
    Elaine W Raines; Fiscal Year: 2013
    ..These studies have the potential to identify biomarkers to recognize patients at risk with chronic inflammatory diseases, and to help determine therapeutic strategies for their treatment. ..
  38. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  39. Beyond PECAM: Mechanisms of Transendothelial Migration
    William A Muller; Fiscal Year: 2013
    ..CD99L2 complement each other's function in vivo? If so, how? Is blocking them therapeutic in models of chronic inflammatory disease? How is LBRC membrane recruited for transcellular migration in vitro and in vivo? ..
  40. Molecular Basis of Mo1 LFA 1 Deficiency
    M Amin Arnaout; Fiscal Year: 2013
    ..Biochemical, immunochemical, genetic and structural approaches and animal models will be utilized by a multidisciplinary group of investigators to achieve these goals. ..
  41. Cardiac Fibrillation: Mechanisms and Therapy
    James N Weiss; Fiscal Year: 2013
    ..Together, these studies will provide critical groundwork necessary to develop and advance novel therapies for this major complication and cause of mortality from heart disease. ..
  42. Histamine and Neutrophil Influx in the Pathogenesis of Acute Lung Injury
    CRAIG ALEXANDER SMUDA; Fiscal Year: 2013
    ..Techniques for therapeutic attenuation of this process are thus of intense clinical interest. This proposal will help to build a theoretical case for or against the use of histamine-directed therapies in clinical management of ALI. ..
  43. VIRAL INFECTION INFLUENCE ON TRANSPLANTATION TOLERANCE
    DALE LESLIE GREINER; Fiscal Year: 2013
    ..This work will identify how infection during transplantation may affect the host immune system and ultimate fate of the graft. ..
  44. Tumor Cell Arrest and Adhesion in the Microcirculation
    Bingmei M Fu; Fiscal Year: 2013
    ....
  45. Vascular Subphenotypes of Lung Disease
    Mark T Gladwin; Fiscal Year: 2013
    ..vascular disease Project 3: Pulmonary vascular-targeted NO therapeutic strategies Core A: Administrative core Core B: Pre-Clinical Models of PAH Core C: Translational Vascular Phenomics, Genomics and Epidemiology Core ..
  46. Improving Cardiac Function After Myocardial Infarction
    Steven R Houser; Fiscal Year: 2013
    ..A gene vector core will generate AAV6 vectors with novel therapeutics for testing in the pig Ml model. An administrative core will ensure data sharing and effective use of all resources. ..
  47. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  48. MOLECULAR BASIS OF CHOLESTEROL METABOLISM
    Joseph L Goldstein; Fiscal Year: 2013
    ..Such an integrated interdisciplinary approach is possible only through continued support of this PPG. ..
  49. New Approaches To Cardiothoracic Tolerance Induction
    Joren C Madsen; Fiscal Year: 2013
    ..We anticipate ongoing progress will continue to contribute to a reduction in the morbidity and mortality associated with solid organ transplantation. ..
  50. Molecular Mechanism of Immune Therapy for Bone Marrow Failures
    Pearlie K Epling-Burnette; Fiscal Year: 2013
    ..Additionally, the efficacy of pharmacological inhibitors to block homing to the bone marrow will be tested to provide critical pre-clinical data for application to clinical studies in patients in the future. ..