2005 |
Mcdowell, Susan A |
R15Activity Code Description: Supports small-scale research projects at educational institutions that provide baccalaureate or advanced degrees for a significant number of the Nation’s research scientists but that have not been major recipients of NIH support. The goals of the program are to (1) support meritorious research, (2) expose students to research, and (3) strengthen the research environment of the institution. Awards provide limited Direct Costs, plus applicable F&A costs, for periods not to exceed 36 months. This activity code uses multi-year funding authority; however, OER approval is NOT needed prior to an IC using this activity code. |
Non Lipid-Lowering Statin Effects Mediated by Pi3k
DESCRIPTION (provided by applicant): Our research focuses on the phosphoinositide 3-kinase (PI3K) family of proteins in the maintenance of cardiovascular health and in the progression of cardiovascular disease. The objective of this research proposal is to better understand intracellular signaling mechanisms and cellular consequences of 3-hydroxy-3-methylgultaryl (HMG) coenzyme A (CoA) reductase inhibitors (statins) mediated by PI3K. Specific PI3K isoforms mediate distinct functions. For example, in the heart, PI3K can stimulate both pathologic and physiologic responses and the key to this apparent discrepancy appears to be based upon which PI3K isoform is activated. The specific aims in this proposal will test the hypothesis that the stimulation of a PI3K isoform or subset of isoforms leads to distinct cell-signaling events in response to simvastatin that are independent of lipid-lowering. The approach will be to address the cellular mechanism of PI3K activation by simvastatin through the use of adenoviral constructs that over-express mutated PI3K isoforms. The role of PI3K in Ca2+ mobilization, activation or inactivation of downstream pathways, and cholesterol-sensitive gene transcription in response to simvastatin will be evaluated. Findings from this work will contribute to the understanding of simvastatin-induced, non lipid-lowering PI3K mediated pathways in human coronary artery endothelium and to significant improvement of current statin treatment.
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0.948 |
2008 |
Mcdowell, Susan A |
R15Activity Code Description: Supports small-scale research projects at educational institutions that provide baccalaureate or advanced degrees for a significant number of the Nation’s research scientists but that have not been major recipients of NIH support. The goals of the program are to (1) support meritorious research, (2) expose students to research, and (3) strengthen the research environment of the institution. Awards provide limited Direct Costs, plus applicable F&A costs, for periods not to exceed 36 months. This activity code uses multi-year funding authority; however, OER approval is NOT needed prior to an IC using this activity code. |
Statins as Inhibitors of Bacterial Host Cell Invasion
[unreadable] DESCRIPTION (provided by applicant): The long-term objective of this research is to understand the molecular mechanisms of bacterial host cell invasion both in vitro and in vivo. Clinical evidence indicates improved prognosis for patients on a statin regimen prior to bacterial sepsis. While some of these beneficial effects have been attributed to improved hemodynamics or immunomodulation, we have recently found that therapeutic concentrations of simvastatin in vitro inhibits host invasion by Staphylococcus aureus, the most common etiologic agent in sepsis. Inhibition appears to be due primarily to the depletion of isoprenoid intermediates by simvastatin within the cholesterol biosynthesis pathway rather than to the depletion of cholesterol itself. Simvastatin also led to the cytosolic accumulation of CDC42 coupled to the phosphoinositide 3-kinase (PI3K) regulatory subunit p85. The proposed hypothesis is that simvastatin inhibits host invasion in part through sequestration of PI3K isoforms within the cytosol. Proposed studies will use genetic approaches to sequester PI3K within the cytosol and assess whether host invasion is decreased. In vivo models of infection will be used to assess whether the inhibition of host invasion increases antibiotic efficacy and prevents chronic, persistent infection, or conversely, whether simvastatin inhibition of uptake by non-professional phagocytes impairs innate clearance. Together, the proposed experiments will address a potentially novel mechanism in the action of statins that could lead to more directed therapeutics to circumvent issues in statin use as an adjunct therapy for infectious disease. The cholesterol-lowering drugs known as statins have a number of non-cholesterol lowering benefits, including a decreased risk of death due to systemic infection. This proposed work will engage undergraduate and master's level students in the investigation of the protective effect of statins, pursuing the question of whether statins block infection, with an overall goal of developing adjunctive therapies for the treatment of infectious disease. PUBLIC HEALTH RELEVANCE: The cholesterol-lowering drugs known as statins have a number of non-cholesterol lowering benefits, including a decreased risk of death due to systemic infection. This proposed work will engage undergraduate and master's level students in the investigation of the protective effect of statins, pursuing the question of whether statins block infection, with an overall goal of developing adjunctive therapies for the treatment of infectious disease. [unreadable] [unreadable] [unreadable]
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0.948 |