Grants and Contracts Details


Individuals with spinal cord injury (SCI) suffer from cardiovascular disease at higher rates than able-bodied individuals. The increased prevalence is often assumed due to decreased activity and increased muscle wasting with SCI. This is assumption is supported by dyslipidemia, or abnormal amounts of lipids (LDL and HDL) in SCI individuals. HDL is normally considered “good cholesterol” due to its ability to drive lipid efflux from macrophages and traffic cholesterol for liver breakdown. In contrast, high levels of LDL are a risk factor for cardiovascular disease. We have new preliminary data indicating that SCI triggers a unique dyslipidemia in which HDL becomes dysfunctional. Specifically, SCI HDL increases lipid accumulation that may worsen inflammation in both the spinal cord and during atherosclerosis. Very few studies explore potential cardiovascular disease mechanisms after SCI outside of lifestyle. Our data indicate that it is possible that traditional approaches employed in able-bodied individuals for treating cardiovascular disease may be less effective in SCI individuals. The identification of SCI HDL as a unique contributor to secondary injury pathology would create a paradigm shift to open new directions for therapeutic development and lead the way for HDL to serve as a biomarker for SCI progression including cardiovascular disease. We propose basic science studies in transgenic animals to provide proof-of-concept data. Dysfunctional HDL has been observed after stroke but is untested in SCI. We hypothesize that SCI HDL triggers a unique disease progression unlike inflammation and cardiovascular disease in abled-bodied individuals. We will comprehensively determine the extent to which SCI HDL (in other words HDL molecules modified and responding to SCI) contribute to intraspinal inflammation and atherosclerosis. The identification of SCI HDL as pathological would be a paradigm shift for the treatment and management of cardiovascular disease and identification of new therapeutic targets for SCI. The cause and effect evidence needed to support a paradigm shift is best gathered in the experimental setting. Given the wealth of clinically viable therapies for cardiovascular disease, we predict that completion of the proposed work has the potential for profound impact on SCI care within 3-5 years of project initiation. To facilitate the implementation of HDL-based therapies in clinical practice we are proposing parallel proof-of-concept studies in humans. Once we gather and report the comprehensive data implicating HDL as therapeutic target, the clinical applicability for cardiovascular disease will be immediate for chronically injured individuals. We will also identify a number of therapies to test in an acute-clinical trial setting which will take longer to reach person-related outcomes. Our predicted products to the SCI community include: (1) the development of new diagnostic targets for assessing cardiovascular disease risk in the SCI patient population; (2) generation of valuable preclinical data for optimizing the therapeutic window of cholesterol altering therapies to avoid unintentional problems and potential side effects caused by dysfunctional SCI HDL; (3) insight into the emerging field of dysfunctional HDL with implications for specific HDL modifications; (4) identification of novel treatment strategies for treating SCI cardiovascular disease which we will demonstrate requires a unique approach vs. cardiovascular disease treatment in able-bodied individuals. The results of clinical trials conducted in able-bodied individuals indicate that HDL-based therapies are largely ineffective. Therefore, without further rationale, this wealth of clinically feasible therapies will not be tested in SCI individuals. The data gathered through the proposed work could be leveraged to ensure that these potentially effective treatments are not lost for SCI. These include: synthetic HDL nano-medicines either resistant to the detrimental modifications specific to SCI or delivered with protective protein components which are identified to be reduced by SCI; ApoA1 Milano recombinant proteins since individuals with this mutation have a reduced risk of cardiovascular disease potentially due to resistance to HDL modification; antioxidant and peroxidize lipid scavengers to protect native HDL from SCI-specific modifications; novel treatments for SCI secondary injury and intraspinal inflammation including those above and use of lipid free ApoA1 to scavenge the phospholipid component of myelin debris. Cardiovascular disease is the second leading cause of death in SCI individuals. The development of therapies that limit the long-term neurological consequences of SCI, either through acute treatment to block secondary injury and cardiovascular disease progression or chronic treatments for atherosclerosis, should lessen overall health care needs of the injured, thereby reducing the burden of families, caregivers, and communities interacting with SCI individuals.
Effective start/end date7/31/2010/30/23


  • Craig H. Neilsen Foundation: $599,000.00


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