Browsing by Department "Medical Physiology"

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Integrins as Regulators of Vascular Contractility in Aged Resistance Arteries
Medical Physiology; TAMU; https://hdl.handle.net/20.500.14641/570; DHHS-NIH-National Institute On Aging
PROJECT SUMMARY Slowing or preventing age-induced arterial vasomotor dysfunction that is associated with an increased risk for cardiovascular diseases remains a significant clinical challenge. Increasing evidence supports that changes in the extracellular matrix alone are insufficient to fully account for vascular stiffness and loss of arterial contractility in aging, and a new concept has emerged that vascular smooth muscle (VSM) cells are important contributors to age-induced arterial dysfunction. The role of integrin-mediated signaling to the regulation of cytoskeletal contractility in the aged VSM cells remains largely unknown. Therefore, there is a critical need to determine the mechanisms whereby age-induced alterations of integrin signaling contributes to decreased vascular contractility in aged resistance arteries. Our long-term goal is to identify mechanisms responsible for the age-induced decline in arterial contractility. The overall objective for this proposal is to determine the mechanistic contribution of integrin signaling to impaired VSM contractility in aged resistance arteries. Our central hypothesis is that age- induced alteration of integrin function impairs recruitment of key adhesion proteins and stress fiber formation resulting in reduced VSM contractility in resistance arteries. We have formulated this hypothesis on the basis of our strong preliminary data indicating that aging decreases key contractile and adhesion proteins. These age- induced changes contribute to the conversion of VSM cells to a synthetic phenotype, which is characterized by reduced VSM cell contractility and mechanosensing in resistance arteries. The rationale for the proposed research is that a mechanistic understanding of how aging affects integrin function and VSM contractility will enable the identification of novel targets to prevent or reverse age-associated loss of vascular contractility. The hypothesis will be tested by pursuing the following two specific aims: (1) Determine the contribution of integrins to the regulation of cell-matrix adhesion in aged VSM; (2) Determine the contribution of integrin signaling to stress fiber formation in aged VSM. The approach will involve the use of real-time, high-resolution fluorescence and atomic force microscopy in live cells, and ex-vivo functional experiments in resistance arteries from young and old, male and female, Fischer 344 rats. The proposed research is innovative because it represents a novel mechanism in aging by which integrin adhesion regulates ROCK/MRTF-A/SRF activation by controlling actin stress fiber formation and actomyosin activation. The proposed research is significant because understanding the mechanism by which integrin function regulates VSM contractility in aged resistance arteries will fill a gap in knowledge regarding age progression. Ultimately, this work will be critical for future studies underlying age- induced loss of contractile function by giving a new direction for therapeutic intervention - vascular remodeling as opposed to blood pressure reduction.
The Role of Hemoglobin Alpha in Diabetes-Related Vascular Dysfunction
Medical Physiology; TAMHSC; https://hdl.handle.net/20.500.14641/551; DHHS-NIH-National Heart, Lung, and Blood Institute
Scientific Abstract Hemoglobin, the oxygen carrying protein expressed in erythrocytes, can be glycated following elevations in blood glucose. Some amino acids, such as the N-terminal valine of the hemoglobin beta chain are highly susceptible to glycation in diabetic patients. This specific glycated isoform, termed HbA1c, has been used by clinicians as an overall picture of a diabetic patient’s ability to control their glucose over a 3-month period and as an indicator for future cardiovascular risks. Recently, it was observed that the alpha chain of hemoglobin, but not the beta chain, is expressed in endothelial cells lining arteries where it interacts with endothelial nitric oxide synthase (eNOS) to modulate nitric oxide (NO) release. Hemoglobin alpha is known to be glycated at a number of sites, including one in the putative eNOS interaction domain. Since it is well recognized that vascular dysfunction underlies many of the pathologies in diabetic patients, it was hypothesized that the hemoglobin alpha expressed in the endothelium will have aberrant function in diabetes mellitus, likely due to a glycation event. The aim of the current proposal is to examine the role of hemoglobin alpha and any possible glycated forms of hemoglobin alpha in the endothelium of a murine model of diabetes. Using pharmacological and genetic approaches, the interaction between hemoglobin alpha and eNOS will be disrupted and the influence on the development of vascular dysfunction will be explored. This work has the potential to identify both a novel biomarker of vascular risk and also a potential therapeutic target for pharmacological treatments.
Use of dietary histidine to counteract lymphatic and mucosal immune dysfunction due to space dysbiosis
Medical Physiology; TAMHSC; https://hdl.handle.net/20.500.14641/583; NASA-Ames Research Center
Dr. Cromer will be responsible for measures of lipid transport, lymphatic leakage, immune cell staining in the mesenteric tissue, antigen uptake studies, and coordination of animal monitoring and health screening. Dr. Endsley will be responsible, as SubRecipient, for the design and training of personnel to complete the immune cell population measurements of the Peyer’s patches and mesenteric lymph nodes and immune cell activation assays. Dr. Alaniz will be responsible for the coordination of FMT procedures, QA/QC of the gnotobiotic facility and the coordination and analysis of microbiome screening