Mechanotransduction pathway activation in familial thoracic aortic aneurysms and dissections

Thoracic aortic aneurysms and dissections (TAAD) are autosomal dominantly inherited in 19% of patients. Mapping studies determined that the disease is genetically heterogeneous with multiple loci and genetic mutations accounting for familial TAAD. However, regardless of the specific mutation, resulting pathology is consistently medial degeneration, characterized by increased proteoglycans and loss of elastic fibers. We tested the hypothesis that genetic mutations leading to familial TAAD alter common pathways in aortic smooth muscle cells (SMCs). Identification of mutations at R460 in TGFBR2 reveals a 5% contribution to TAAD, however downstream analysis of Smad2 phosphorylation in the TGF-β pathway is not commonly altered in familial or sporadic disease when compared to controls. Expression profiling using Illumina's Sentrix HumanRef 8 Expression Beadchip array was done on RNA isolated from SMCs explanted from 6 patients with inherited TAAD with no identified mutation and 3 healthy controls obtained from the International Institute for the Advancement of Medicine. Significant increases in expression of proteoglycan genes in patients' SMCs, specifically lumican, podocan, and decorin were confirmed using Q-PCR and tissue immunofluorescence. NCI's Ingenuity Pathway Analysis predicted alterations in the ERK, insulin receptor and SAPK/JNK pathways (p<0.001), which SMCs activate in response to cyclic stretch. Immunoblotting indicated increased phosphorylation of ERK and GSK-3β, a protein from the insulin receptor pathway, in explanted patient SMCs, also confirmed by increased immunoreactivity against phosphorylated ERK and GSK-3β in the sub-intimal SMCs from patient tissue compared to controls. To determine if mechanotransduction pathway activation was responsible for the medial degeneration a specific inhibitor of GSK-3β, SB216763 was incubated with control cells and significantly increased the expression levels of proteoglycans. Mechanical strain was also applied to control SMCs confirming pathways stimulation with stretch. Incubation with pathway inhibitors against insulin receptor and ERK pathways identify, for the first time that stretch induced GSK-3β phosphorylation may increase proteoglycan expression, and ERK phosphorylation may regulate the expression of MMP2, a protein known to degrade elastic fibers. Furthermore, specific mutations in SMC-specific β-myosin heavy chain and α-actin, in addition to upregulation of pathways activated by cyclic stretch suggest that SMC response to hemodynamic factors, play a role in this disease. ^

AN OCCUPATIONAL INJURY MANAGEMENT INFORMATION SYSTEM FOR THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON

The purpose of this research and development project was to develop a method, a design, and a prototype for gathering, managing, and presenting data about occupational injuries.^ State-of-the-art systems analysis and design methodologies were applied to the long standing problem in the field of occupational safety and health of processing workplace injuries data into information for safety and health program management as well as preliminary research about accident etiologies. The top-down planning and bottom-up implementation approach was utilized to design an occupational injury management information system. A description of a managerial control system and a comprehensive system to integrate safety and health program management was provided.^ The project showed that current management information systems (MIS) theory and methods could be applied successfully to the problems of employee injury surveillance and control program performance evaluation. The model developed in the first section was applied at The University of Texas Health Science Center at Houston (UTHSCH).^ The system in current use at the UTHSCH was described and evaluated, and a prototype was developed for the UTHSCH. The prototype incorporated procedures for collecting, storing, and retrieving records of injuries and the procedures necessary to prepare reports, analyses, and graphics for management in the Health Science Center. Examples of reports, analyses, and graphics presenting UTHSCH and computer generated data were included.^ It was concluded that a pilot test of this MIS should be implemented and evaluated at the UTHSCH and other settings. Further research and development efforts for the total safety and health management information systems, control systems, component systems, and variable selection should be pursued. Finally, integration of the safety and health program MIS into the comprehensive or executive MIS was recommended. ^

Pathway Semantics: An Algebraic Data Driven Algorithm to Generate Hypotheses about Molecular Patterns Underlying Disease Progression

The overarching goal of the Pathway Semantics Algorithm (PSA) is to improve the in silico identification of clinically useful hypotheses about molecular patterns in disease progression. By framing biomedical questions within a variety of matrix representations, PSA has the flexibility to analyze combined quantitative and qualitative data over a wide range of stratifications. The resulting hypothetical answers can then move to in vitro and in vivo verification, research assay optimization, clinical validation, and commercialization. Herein PSA is shown to generate novel hypotheses about the significant biological pathways in two disease domains: shock / trauma and hemophilia A, and validated experimentally in the latter. The PSA matrix algebra approach identified differential molecular patterns in biological networks over time and outcome that would not be easily found through direct assays, literature or database searches. In this dissertation, Chapter 1 provides a broad overview of the background and motivation for the study, followed by Chapter 2 with a literature review of relevant computational methods. Chapters 3 and 4 describe PSA for node and edge analysis respectively, and apply the method to disease progression in shock / trauma. Chapter 5 demonstrates the application of PSA to hemophilia A and the validation with experimental results. The work is summarized in Chapter 6, followed by extensive references and an Appendix with additional material.