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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Molecular investigations of BtK and WASP

MacCarthy-Morrogh, Lucy January 1998 (has links)
No description available.
2

Structural study of the WH2 family and filamin : implications for actin cytoskeleton regulation /

Aguda, Adeleke H., January 2006 (has links)
Diss. (sammanfattning) Uppsala : Uppsala universitet, 2006. / Härtill 3 uppsatser.
3

Unraveling the Functions of Wiskott-Aldrich Syndrome Protein: Insights into RNA Splicing, Nucleolus Regulation, and Immunosenescence

Zhou, Xuan 08 1900 (has links)
The Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency characterized by microthrombocytopenia, eczema, recurrent infections, autoimmunity, and predisposition to malignancy. Mutations in the WAS gene lead to dysfunction of the Wiskott-Aldrich syndrome protein (WASP), a multifunctional regulator implicated in various hematopoietic and immune processes. While some disease phenotypes have been linked to classical WASP's actin nucleation function, recent advances have unveiled additional nuclear functions, such as involvement in R-loop formation, transcriptional regulation during T helper 1 cell differentiation, and homology-directed repair. However, a comprehensive understanding of WASP's multifaceted functions remains elusive. We employ induced pluripotent stem cells (iPSCs) and Clustered Regularly Interspaced Palindromic Repeats (CRISPR) technology, specifically the CRISPR-Cas9 system, as powerful tools to investigate the mechanisms underlying WASP's functions. We first explore the consequences of WASP loss on RNA splicing. We reveal its critical role in RNA splicing. WASP-deficiency causes widespread alterations RNA splicing patterns and epigenetic activation of splicing factor gene promoters. Additionally, we uncover its involvement in liquid-liquid phase separation, forming phase-separated condensates to dynamically regulate the splicing machinery. In the second part of this thesis, our investigation uncovers the presence of WASP within the nucleolus and its interactions with key nucleolar proteins. Intriguingly, depletion of WASP leads to significant reduction in nucleolar size, disrupted nucleolar morphology, and decreased ribosomal RNA transcription, unveiling its critical role in nucleolus structure and function. Furthermore, we successfully recapitulated nucleolus changes and ribosomal RNA profile in patient samples. Lastly, we investigate immunosenescence, a crucial aspect of aging-related immune dysregulation, in the context of WAS. Through the use of WASP-deficient macrophage cells, our study revealed several distinctive features associated with immunosenescence in WASP-KO-iMPs. These include increased senescent cell proportions, heightened expression of senescence-associated secretory phenotype genes, nuclear deformation, loss of heterochromatin, and enhanced susceptibility to DNA damage. These preliminary findings offer valuable insights into our understanding of immunosenescence within the framework of WASP-deficient macrophages and its association with conditions related to WAS. In conclusion, the mechanistic study of WASP has unveiled its novel roles in regulating RNA splicing, nucleolus structure and function, as well as its potential involvement in immunosenescence.
4

Regulation of B cell motility and adhesion in health and disease /

Westerberg, Lisa, January 2003 (has links)
Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 4 uppsatser.
5

Biochemical and biophysical characterization of the allosteric equilibrium of the Wiskott-Aldrich Syndrome protein

Leung, Daisy W. January 2005 (has links)
Thesis (Ph.D.) -- University of Texas Southwestern Medical Center at Dallas, 2005. / Embargoed. Vita. Bibliography: References located at the end of each chapter.
6

Development Of Wiskott-Aldrich Syndrome Knock Out Protocol For Drug Substance Assay Development

Hanna, Julia C 01 June 2023 (has links) (PDF)
Wiskott-Aldrich Syndrome (WAS) is a rare X-linked primary immunodeficiency affecting approximately 1 in 100,000 live XY births in North America and is caused by a mutation to the WAS gene which is expressed across hematopoietic lineages. The WAS protein (WASp) plays a role in regulating actin polymerization. On a cellular level, there are a variety of effects of a lack of WASp or expression of a dysfunctional WASp protein for patients including issues with migration, adhesion, chemotactic response, phagocytosis, activation, and proliferation across different cell types in addition to reduced platelet size and output. This can lead to several systematic effects for the patients however because mutations to the WAS gene are not limited to one location or type there is a great amount of variability between patient symptoms making it challenging to diagnose. Major symptoms include frequent and recurrent infections, uncontrolled bleeding episodes, issues associated with autoimmunity, and malignancy, the most common form being lymphoma. Without treatment, the life expectancy of an individual diagnosed with WAS is 14 years of age, and the only curative treatment strategy available is hematopoietic stem and progenitor cell transfer (HSPCT). If not performed with an HLA-identical donor, which is available to less than 10% of patients, and within the first two years of life, the risk of graft versus host disease (GvHD) increases drastically for the patient. A gene therapy using autologous and genetically corrected CD34+ cells would be advantageous to the patients due to a reduction in preparative conditioning, immunosuppressive aftercare, and the risk of GvHD. CSL Behring is currently in the development of a lentiviral gene therapy to fulfill this gap in care, however, to develop the assays required to assess and characterize the drug substance usually an uncorrected patient sample is compared with a gene-edited sample. The limitation here is that due to the risk of infection and bleeding patient sample is very limited and therefore the development of a mock patient sample is necessary for early development. The goal of the project is to develop a WAS-KO protocol utilizing CRISPR/Cas9 and its characterization.
7

CD4+ Foxp3+ regulatory T cell homing & homeostasis /

Sather, Blythe Duke. January 2007 (has links)
Thesis (Ph. D.)--University of Washington, 2007. / Vita. Includes bibliographical references (leaves 122-140).
8

Structure, function and evolution of human subtelomeres /

Linardopoulou, Elena, January 2005 (has links)
Thesis (Ph. D.)--University of Washington, 2005. / Vita. Includes bibliographical references (leaves 214-243).
9

Mechanistic Studies of Human Immune Disease Relevant Genes and CRISPR Genome Editing Using Stem Cells

Yuan, Baolei 11 1900 (has links)
Stem cells, with the ability to self-renew and differentiate into intended cell types, are a valuable tool for disease modeling and mechanistic study. CRISPR-Cas9 has been widely used for genome editing due to its high efficiency and convenience. However, CRISPR-Cas9 has large-deletion safety issues that dramatically restrict its applications. Wiskott-Aldrich syndrome (WAS) is an inborn immunological disorder caused by WASP deficiency. WASP functions in the nucleus, which may help to understand WAS pathology, are poorly defined. Pannexin 1 (PANX1) forms large plasma membrane pores to exchange intracellular small molecules with the extracellular environment and functions in inflammatory processes. The regulatory mechanisms of the PANX1 channel remain obscure. In this dissertation, I focused on mechanistic studies of CRISPR-Cas9 genome editing, and two immune disease relevant genes, WASP and PANX1 using stem cell-derived immune cells. We first found that CRISPR-induced large deletions (LDs) are predominantly mediated by the MMEJ repair pathway through statistical studies. Further, we found POLQ and RPA play vital roles in CRISPR-induced LDs. Modulation of POLQ and RPA can decrease CRISPR-induced LDs and increase HDR efficiency. Using three isogenic WAS iPSC models generated via gene editing, we successfully recapitulated WAS phenotypes, and for the first time, revealed that WASP regulates RNA splicing via epigenetically controlling the transcription of splicing factors and directly participating in the splicing machinery through a liquid-liquid phase separation process. We established a full-length human PANX1 (hPANX1) channel model via cryo-electron microscopy experiments and molecular dynamics simulation study, and found that hPANX1 channel is a homo-heptamer with both the N- and C-termini stretching deeply into the pore funnel. Functional studies of three selected residues support the new hPANX1 channel model and suggest the potential regulatory role of hPANX1 in pyroptosis upon immune responses. Overall, the mechanistic studies of WASP, PANX1 and CRISPR genome editing revealed new roles of WASP in regulating RNA splicing, new functional insights of PANX1 in pyroptosis, and uncovered two critical players POLQ and RPA in CRISPR-induced LDs.
10

The characterization of the cytoskeleton and associated proteins in the formation of wound-induced contractile arrays /

Stromme, Adrianna. January 2008 (has links)
The cytoskeleton is an intrinsic aspect of all cells, and is essential for many cellular events including cell motility, endocytosis, cell division and wound healing. Remodeling of the cytoskeleton in response to these cellular activities leads to significant alterations in the morphology of the cell. One such alteration is the formation of an actomyosin contractile array required for cytokinesis, wound healing and embryonic development. / Cellular structure and shape depends upon tensional prestress brought about by the organization of cytoskeletal components. Using the Xenopus laevis oocyte wound healing model, it is first described how diminished cellular tension affects the balance of the Rho family of GTPases, and subsequently prevents the formation of actomyosin contractile arrays. This suggests that cellular tension in the cell is not created at the level of the cytoskeletal elements but rather via the upstream signaling molecules: RhoA and Cdc42. / The role of N-WASP (Neural-Wiscott Aldrich Syndrome Protein), a mediator of Arp2/3 based actin polymerization, is next examined for its putative role in cellular wound healing. Xenopus laevis oocytes injected with mutant N-WASP constructs reveals in vivo evidence that functional N-WASP is required for appropriate contractile array formation and wound closure. / Lastly, it is revealed that the cellular structures involved with single cell wound healing in other model systems are also important for the initial repair of severed muscle cells. Actin, non-muscle myosin-II, microtubules, sarcomeric myosin and Cdc42 are all recruited and reorganized at the edge of damaged C2C12 myotubes. This data promotes the possibility that an actomyosin array may be established in injured muscle cells as well.

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