Towards experimental therapies for retinal degenerative diseases

This thesis describes part of the preclinical road that is essential in developing experimental therapies for retinal degenerative diseases such as age-related macular degeneration (AMD) and a specific type of retinitis pigmentosa (RPE-RP). The retinal pigment epithelium (RPE) plays a significant role in the pathology of both diseases. Indeed, patients of all ages can be affected by conditions involving (primarily) the RPE. This thesis is focused on RPE disease pathology, illustrated by the complex retinal disease AMD and a specific genetic form of the monogenic disorder RP. Many experimental therapeutic strategies are being developed to treat AMD and RPE-RP; however, gene therapy and cell-replacement therapy can be considered important strategies for these diseases, especially because of the curative nature of these two treatment modalities. In this thesis, we first used a systematic approach to identify and analyze all preclinical studies that have been published regarding RPE cell-replacement strategy to treat retinal degenerative diseases (Chapter 2). We next used a genome-editing technique to create a new animal model for an RPE-RP subtype and characterized the model in-depth (Chapter 3). Additionally, we describe an induced preclinical model for AMD and its in-depth characterization (Chapter 4). As a final step, we describe the generation of a 3D-bio-printed tissue recapitulating the RPE and underlying tissues and its transplantation and integration into rat eyes (Chapter 5)

An examination of the impact of dietary lipids on behaviour and neurochemistry

The molecular and cellular basis of stress pathology remains an important research question in biological science. A better understanding of this may enable the development of novel approaches for the treatment of stress-related disorders. There is a considerable body of scientific evidence suggesting that dietary lipids, phospholipids and omega-3 polyunsaturated fatty acids (n-3 PUFAs), have therapeutic potential for certain psychiatric disorders. Thus, we proposed n-3 PUFAs as a novel strategy for the prevention or amelioration of stress-related disorders. We hypothesised that these compounds would improve behavioural and neurobiological responses and alter gut microbial composition. Furthermore, we proposed a new mechanism of action exerted by n-3 PUFAs using an in vitro model of stress. Lastly, we explored the protective effects of both phospholipids and n-3 PUFAs against neuroinflammation, which has been shown to contribute to the development of stress-related disorders. We provide further evidence that glucocorticoids, inflammation and early-life stress induce vulnerability to psychopathologies. Specifically, we have demonstrated that corticosterone (CORT) alters cortical neuron and astrocyte percentage composition, reduces brain-derived-neuronal factor (BDNF) expression, and induces glucocorticoid receptor (GR) down-regulation in mixed cortical cultures. Interestingly, we found that lipopolysaccharide (LPS) treatment resulted in an over-expression of pro-inflammatory cytokines in cortical astrocyte cultures. Moreover, we demonstrate that early-life stress induces changes to the monoaminergic and immune systems as well as altered neuroendocrine response to stressors later in life. In addition, we found that early-life stress alters the gut microbiota in adulthood. These data demonstrate that n-3 PUFAs can attenuate CORT-induced cellular changes, but not those caused by LPS, within the cerebral cortex. Similarly, phospholipids were unable to reverse LPS-induced inflammation in cultured astrocytes. In addition, this thesis proposes that n-3 PUFAs may prevent the development or lessen the symptoms of mental illnesses, ameliorating anxiety- and depressive-like symptoms as well as cognitive effects, particularly when administered during neurodevelopment. Such effects may be mediated by GR activation as well as by modification of the gut microbiota composition. Taken together, our findings suggest that n-3 PUFAs have therapeutic potential for stress-related disorders and we provide evidence for the mechanisms by which they may exert these effects. These findings contribute to an exciting and growing body of research suggesting that nutritional interventions may have an important role to play in the treatment of stress-related psychiatric conditions

Faculty Publications and Creative Works 2001

One of the ways in which we recognize our faculty at the University of New Mexico is through Faculty Publications & Creative Works. An annual publication, it highlights our faculty\u27s scholarly and creative activities and achievements and serves as a compendium of UNM faculty efforts during the 2001 calendar year. Faculty Publications & Creative Works strives to illustrate the depth and breadth of research activities performed throughout our University\u27s laboratories, studios and classrooms. We believe that the communication of individual research is a significant method of sharing concepts and thoughts and ultimately inspiring the birth of new ideas. In support of this, UNM faculty during 2001 produced over 2,299* works, including 1,685 scholarly papers and articles, 69 books, 269 book chapters, 184 reviews, 86 creative works and 6 patented works. We are proud of the accomplishments of our faculty which are in part reflected in this book, which illustrates the diversity of intellectual pursuits in support of research and education at the University of New Mexico

Workshop on Squeezed States and Uncertainty Relations

The proceedings from the workshop are presented, and the focus was on the application of squeezed states. There are many who say that the potential for industrial applications is enormous, as the history of the conventional laser suggests. All those who worked so hard to produce squeezed states of light are continuing their efforts to construct more efficient squeezed-state lasers. Quite naturally, they are looking for new experiments using these lasers. The physical basis of squeezed states is the uncertainty relation in Fock space, which is also the basis for the creation and annihilation of particles in quantum field theory. Indeed, squeezed states provide a unique opportunity for field theoreticians to develop a measurement theory for quantum field theory

Novel Anti-cancer Agents and Cellular Targets and Their Mechanism(s) of Action

Patient outcomes remain poor for many cancers despite improvements in treatments and new molecular-targeted biomedicines for certain cancer types or subtypes. Dose-limiting toxicity, a narrow therapeutic index, and the development of resistance to traditional anti-cancer agents are well-established. It is apparent that inherent and acquired drug resistance are major challenges with molecular-targeted agents and that on- as well as off-target side effects can still occur. Other issues include drug metabolism by the body and safely supplying a sufficient amount of active drug to the tumor cells. There is a clear and urgent need for new molecular targets and drugs that specifically target cancer cells in different ways to existing approved drugs. This book, through a collection of eight research articles and two review articles from the Biomedicines themed Special Issue ‘Novel Anti-Cancer Agents and Cellular Targets and Their Mechanism(s) of Action’, provides a snapshot of some of the diverse and exciting research approaches being taken by the cancer research community in trying to address some of these therapeutic challenges

Reconstituted collagen fibres for tissue engineering applications

In vitro, under appropriate conditions collagen molecules spontaneously form fibrils (fibrillogenesis) with the characteristic D-periodic banding similar to native fibrils. Recently, reconstituted collagen fibres have been of interest. Due to their unique advantageous properties, such as high surface area, softness, absorbency and ease of fabrication into many product forms, biomaterial based on reformed collagen fibres have been used as a substrate for nerve regeneration, tendon and ligament replacement, wound dressing applications and suture materials. Although some work has been done, still there is little understanding of the factors affecting the physical properties of such fibres. Therefore, the aim of the work presented in this thesis was to study and better understand the influence of factors which control the structure and physical properties of extruded reconstituted collagen fibres. Acid and pepsin soluble collagen was extracted from different animal species (bovine Achilles tendon, rat tail tendon and pig tail tendon) and was extruded, using different internal diameter laboratory tubes into a series of neutral buffers, comprised of different co-agents such as sodium chloride, different molecular weight of polyethylene glycols and poly vinyl alcohols at 37°C, where fibrillogenesis occurred. After 15 minutes incubation, the fibres were washed and air-dried under the tension of their own weight. In addition, an extensive study of the effects of a wide range of cross-linking techniques (chemical, physical, biological and natural) was undertaken. The structural, mechanical (dry and wet) and thermal properties of the reconstituted collagen fibres were evaluated using optical and scanning electron microscopy, tensile mechanical tests and differential scanning calorimetry respectively. In general, it was found that the properties of the reformed collagen fibres were dependent on pre- (animal species, extraction method, collagen concentration) during- (fibre formation medium) and post- (cross-linking) fibre formation variables. A strong correlation between fibre diameter and stress at break was observed throughout this work; by increasing the diameter of the fibre either by increasing the collagen concentration, the tube internal diameter, the amount of the co-agent or via cross-linking, a decrease of the tensile strength at break was observed. The thermal properties of the matrices appeared to be dependent on the cross-linking technique utilized. Overall, it was demonstrated that reconstituted collagen fibres can be tailor made to suit a diversity of surgical needs with properties similar to or even superior to native tissues or other synthetic materials that are already in practice