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Characterisation of the TSCI candidate region on human chromosome 9q34Woodward, Karen Jane January 1995 (has links)
No description available.
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Use of irradiation hybrids in gene mapping on human chromosome IIGillett, Godfrey Tregelles January 1999 (has links)
No description available.
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Identification and analysis of mutations in the TSC1 geneJeganathan, Dharini January 2000 (has links)
No description available.
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A role for the tuberous sclerosis-2 tumor suppressor gene in quinol-thioether-induced nephrocarcinogenicity in the Eker rat /Yoon, Hae-seong, January 2000 (has links)
Thesis (Ph. D.)--University of Texas at Austin, 2000. / Vita. Includes bibliographical references (leaves 153-184). Available also in a digital version from Dissertation Abstracts.
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Regulation of bone by the MTORC1 pathway in osteoclasts and osteocytesZgoda, Molly Flynn 18 June 2019 (has links)
Bone is a highly dynamic organ system comprised of various cell types that are constantly working to maintain the health and stability of bone. The main cells involved are the osteoblasts that form bone, the osteoclasts that degrade bone, and the osteocytes that act as sensors of the microenvironment and coordinate a response. An imbalance of the interactions between the cell types can potentially result in pathological states in bone at the microscopic level that can then affect the entire skeleton. Moreover, a number of genetic mutations can also lead to pathogenic changes in bone. An example of such is the development of sclerotic bone lesions in patients with the disease tuberous sclerosis complex.
Tuberous sclerosis complex, or TSC, is an autosomal dominant disorder affecting approximately 1.5 million people worldwide. It is caused by a mutation in one of the genes encoding either member of the TSC1-TSC2 complex. Molecularly, TSC1-TSC2 negatively regulate the mechanistic target of rapamycin (mTOR) kinase in the mutli-protein complex mTORC1. Activation of mTORC1 leads to an upregulation of protein synthesis and cell growth. Tuberous sclerosis patients are heterozygous for TSC1 or TSC2, and post-natal loss of the second allele results in the development of multiple, benign, tumor-like hamartomas in various organ systems, most notably affecting the brain, kidneys, lungs, skin, and heart. Additionally, CT scans of patients reveal multiple loci of dense, compact bone termed sclerotic bone lesions. The bone lesions were most commonly seen in the posterior elements of the vertebrae and while they are asymptomatic, a remarkably high frequency of patients express them.
To further investigate and better understand the mechanisms of tuberous sclerosis complex in bone, we analyzed a mouse model with heterozygous deletion in Tsc2. Initial examination showed the Tsc2+/- mice recapitulated tumors in various organ systems, most notably the kidney, and presented bone lesions in the pelvis and elements of the vertebrae. To further investigate the mechanism driving the disease state, we used a Cre driver thought to be specific for osteoclast (Cathepsin K-Cre, or Ctsk-Cre) to selectively delete Tsc2. Cathepsin K-Cre; Tsc2fl/fl mice exhibit a remarkably high bone mass. This study examined three specific aspects of this high bone mass phenotype. First, we sought to verify that the increased bone mass caused by Ctsk-Cre driven Tsc2 deletion was dependent on mTORC1 upregulation. This was done by generating Ctsk-Cre;Tsc2fl/fl mice lacking Raptor, a mTORC1 component essential for function. Next, we investigated the cell of origin driving the increase bone density by utilizing additional Cre drivers specific for osteoclasts and osteocytes. Additionally, we used radiation chimeras to assess if donated wild type cells could rescue the observed phenotype. We lastly explored the role of a secreted signaling molecule, CTHRC1, that has been proposed as a candidate to mediate osteoclast-osteoblast interaction, in the high bone mass phenotype of Ctsk-Cre;Tsc2fl/fl mice.
Selective deletion of Tsc2 in bone cells provides an excellent model to investigate pathways regulating bone mass and strength and may provide new candidate targets for treating diseases of low bone mass, such as osteoporosis.
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Regulation and function of tuberous sclerosis complex-2 tumor suppressor in renal cell carcinomaLiu, Yu, Walker, Cheryl, Richburg, John H., January 2004 (has links)
Thesis (Ph. D.)--University of Texas at Austin, 2004. / Supervisors: Cheryl L. Walker and John H. Richburg. Vita. Includes bibliographical references. Also available from UMI.
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Tuberous Sclerosis-associated enamel pitting and gingival fibromas: Familial vs. sporadic disease; genotype-phenotype correlationsDock, Murray January 2000 (has links)
Indiana University-Purdue University Indianapolis (IUPUI) / The purpose of this investigation was to study the incidence of enamel pitting and gingival fibromas in patients with tuberous sclerosis complex (TSC) and relate these findings to other physical findings of TSC, to sporadic and familial disease, and to specific TSC2 mutations. Methods: A total of 104 patients between 1 and 51 years of age were examined for enamel pits and gingival fibromas. All study subjects had a definitive diagnosis of TSC and were participants in a related study that provided results from MRI scans of the brain, echocardiography, renal ultrasound, neuropsychological assessments, and retinal examinations. Blood samples were obtained from each participant for DNA extraction and subsequent TSC mutational analysis. Results: Enamel pitting was seen in 29% of patients between 1 and 6 years of age, in 90% between 6 and 13 years of age, and in 100% of patients in the permanent 113 dentition. The majority of the pits were pinpoint sized and primarily affected the maxillary anterior arch. The maxillary central incisor was the most often affected permanent tooth and the maxillary canine was the most often affected primary tooth. Gingival fibromas were apparent in 47% of subjects in the mixed dentition and in 70% of subjects in the permanent dentition. Only one patient out of 31 in the primary dentition had a gingival fibroma. The majority of fibromas affected the interdental papilla of the maxillary anterior arch. There were few significant findings relating the degree and/or severity of enamel pitting and/or gingival fibromas to other physical findings of TSC. Enamel pitting in primary as well as permanent teeth were found to be strongly related to the presence of facial angiofibromas and a somewhat weaker association was seen with cardiac arrhythmias. Gingival fibromas were strongly related to the presence of facial angiofibromas and more weakly related to retinal lesions. There were no distinctions
apparent between oral findings in sporadic and familial TSC nor were there any genotype-phenotype correlations between oral findings and TSC2 mutations. Conclusion: The combination of enamel pitting and gingival fibromas, as minor
features of TSC, should raise the suspicion level regarding tuberous sclerosis as a
diagnosis. Both are important minor features frequently seen which may help in
establishing a definitive diagnosis. Scanning the dentition and gingiva is noninvasive, is
inexpensive, and should be included in evaluating all patients suspect of a diagnosis of
tuberous sclerosis.
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Associação entre hemimegalencefalia e esclerose tuberosa em pacientes com epilepsia / Association between hemimegalencephaly and tuberous sclerosis in patients with epilepsyCoutinho, Larissa Cristina de Queiroga Mendonça 20 June 2018 (has links)
Introdução: A hemimegalencefalia é uma rara malformação cerebral que envolve o crescimento anormalmente maior de um hemisfério cerebral. Clinicamente, observase macrocefalia, retardo mental, hemiparesia contralateral, hemianopsia e epilepsia intratável. A Esclerose tuberosa é uma doença genética rara, multissistêmica, caracterizada por tumores benignos e manifesta-se clinicamente com epilepsia e atraso cognitivo. A associação das duas patologias é rara, requer acompanhamento multidisciplinar e tratamentos medicamentoso e cirúrgico específicos. Objetivos: Identificar a presença de hemimegalencefalia em pacientes portadores de esclerose tuberosa com epilepsia atendidos no Centro de Cirurgia de Epilepsia (CIREP) do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo. Realizar revisão de literatura sobre esclerose tuberosa e hemimegalencefalia, assim como a associação entre elas. Material e Métodos: Foi realizada revisão da literatura sobre esclerose tuberosa e hemimegalencefalia e também dos prontuários de pacientes que apresentam associação entre essas patologias. Resultados: Foram analisadas 1534 monitorizações por videoeletroencefalograma (VEEG) em crianças e adolescentes no CIREP. Dessas, 25 apresentavam hemimegalencefalia, e apenas duas com esclerose tuberosa associada. Foram, então, relatados os casos com descrição das etapas de avaliações pré-operatórias, cirurgia para o tratamento da epilepsia, e poslterior seguimento clínico, e também dos exames de imagem, neurofisiológicos e neuropatológicos. Conclusões: A associação entre hemimegalencefalia e esclerose tuberosa é uma manifestação rara, com apenas seis casos descritos na literatura. Contudo, tratandose de associação entre as doenças, a abordagem terapêutica e o seguimento dessas crianças com hemimegalencefalia se modifica, tanto na investigação quanto no acompanhamento clínico das manifestações sistêmicas da esclerose tuberosa. Os dois casos descritos apresentaram espasmos assimétricos, sendo iniciado tratamento com vigabatrina e posterior indicação cirúrgica. / Introduction: Hemimegalencephaly is a rare brain malformation that involves an abnormally larger growth of one cerebral hemisphere. Clinically, macrocephaly, mental retardation, contralateral hemiparesis, hemianopsia and intractable epilepsy are observed. Tuberous sclerosis is a rare, multisystemic genetic disease characterized by benign tumors and clinically manifested with epilepsy and cognitive delay. The association of these two pathologies is rare, requiring multidisciplinary care and specific drug and surgical treatment. Objectives: To identify the presence of hemimegalencephaly in patients with tuberous sclerosis with epilepsy attended at the Center for Epilepsy Surgery (CIREP, acronym in Portuguese) of the Clinics Hospital of Ribeirão Preto Medical School. To perform a literature review on tuberous sclerosis and hemimegalencephaly, as well as the association between them. Material and Methods: Review of the literature on tuberous sclerosis and hemimegalencephaly; review of patient records that show the association between these pathologies. Results: 1534 monitoring by VEEG in children and adolescents in CIREP were analyzed. Of these, 25 had hemimegalencephaly, and only two had associated tuberous sclerosis. The cases were reported with descriptions of the stages of preoperative evaluations, surgery for the treatment of epilepsy, with subsequent clinical care, as well as image, neurophysiological and neuropathological examinations. Conclusions: The association between hemimegalencephaly and tuberous sclerosis is a rare manifestation, with only six cases described in the literature. However, considering that it is an association between diseases, the therapeutic approach and the follow-up of these hemimegalencephalic children are specified, both in the investigation and in the clinical care of the systemic manifestations of tuberous sclerosis. Both described cases presented asymmetrical spasms, initiated treatment with vigabatrin with subsequent surgical indication and both presented renal alterations.
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Regulation and function of tuberous sclerosis complex-2 tumor suppressor in renal cell carcinomaLiu, Yu, 1975- 03 August 2011 (has links)
Not available / text
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Regulation of osteoclast differentiation and activation in response to environmental stimuliLiu, Haoming 13 July 2017 (has links)
Bone is a biomaterial composed of organic and inorganic molecules that are continuously remodeled to preserve structural integrity and allow adaptation to stress. Two major types of cells are responsible for this process: the osteoblast that synthesizes the bone and the osteoclast that resorbs the bone. A delicate balance between the function of these two cell types is required to maintain proper bone health and body homeostasis.
Three independent projects were conducted to investigate the functions of osteoclasts in response to manipulations of their environment. The differentiation and activation of osteoclasts depends largely on cell-cell communication and integration of signals such as stress and metabolic status. The canonical pathway of osteoclast differentiation is driven by receptor activator of NFKB ligand (RANKL), a cytokine produced in large part by cells of the osteoblast lineage. In inflammatory states, RANKL is also made by T cells and synovial cells in the joint. In addition to altering RANKL, inflammation may enhance osteoclast formation through various other cytokines. In project one, we examined the effect of inflammatory cytokine interleukin (IL)-X in a mouse inflammatory arthritis model and found that it is not required for osteoclast activity. Previous studies have reported that other inflammatory cytokines, including as TNF and IL-6 are able to induce osteoclast differentiation in mice, in addition to the RANKL pathway. Project two investigates whether these cytokines could have the same function in humans. In addition to inflammatory cytokines, osteoclasts have been shown to respond to extracellular stimuli such as stress and metabolic status. Factors responsible for integrating these signals, TSC2 and the mTORC1 complex, were investigated for their role in osteoclast activity, regulation of communication between osteoclasts and osteoblasts, and subsequent formation of a high bone mass phenotype.
All three projects have clinical correlations in human. Studying the effects of inflammatory cytokines could reveal mechanisms and strategies for prevention of erosions in rheumatoid arthritis and other inflammatory arthritidies. Heterozygous mice for the Tsc2 gene can be used as a mouse model for diseases including tuberous sclerosis complex and Paget’s disease. Moreover, understanding the role of mTORC1 complex activity in regulating bone mass could shed light on the potential effect of long-term rapamycin treatment for patients. As demonstrated through these projects, bone is highly dynamic and regulated by numerous physiological processes.
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