Sunday, May 11, 2025
5/11/2025
VASCULAR TARGETING OF OXIDATIVE STRESS - DESCRIPTION (provided by applicant): Insulin resistance, a prominent feature of metabolic syndrome, leads to impairments in perfusion of metabolically active tissues and organs and contributes to cardiovascular morbidity and mortality.. Elevated oxidative stress has been implicated in the development of vascular insulin resistance. Recent work shows that bispecific antibodies can be used to target adenovirus specifically to the endothelium. In this project we will use adenoviruses targeted to the vascular endothelium in order to determine the roles and sources of oxidative stress in the development of insulin resistance. The Specific Aims of this proposal are: 1. To determine the tissue and cellular distribution patterns resulting from systemic infusion of adenovirus conjugated to vascular targeted bi-specific. 2. To determine the effects of anti-oxidant gene delivery on insulin resistance and vascular function in a rat model of metabolic syndrome. In this exploratory project we will construct and validate several bispecific antibodies designed to deliver adenovirus to the endothelium. Each will consist of one moiety designed to bind the adenoviral knob and block uptake by cells, such as hepatocytes, which usually sequester adenovirus. The other moiety will be designed to bind epitopes expressed on the endothelium, thereby facilitating uptake by the vasculature. Each construct will be tested, in vitro, for binding to endothelial antigens and, in vivo, for the ability to deliver adenovirus specifically to vascular tissues. The construct with the most efficient targeting of the vasculature will be used for subsequent in vivo studies. We will use the fructose-fed stroke-prone spontaneously hypertensive rats (SHRSP) displaying dyslipidemia, and insulin resistance. Adenoviruses encoding genes designed to either reduce the production or increase the removal of SO will be conjugated with the optimized bispecific antibody and infused systemically into SHRSP. The effects on levels of reactive oxygen species in vascular tissues will be measured and function of conduit and resistance vessels will be determined and glucose tolerance tests performed. Development of a bispecific antibody to target anti-oxidant genes delivery to the endothelium will result in a more precise understanding of the role of oxidative stress in the development of insulin resistance and generate a more rational design of new drugs, and utilization of existing ones, to provide a coherent therapeutic regime for individuals with metabolic syndrome. PUBLIC HEALTH RELEVANCE: This project develops methods designed to increase our understanding of why the modern lifestyle is resulting in the increased development of cardiovascular disease. A greater appreciation of the underlying mechanisms will undoubtedly contribute to improved recommendation to the general public regarding diet and activity.
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