2013 |
Wood, Susan Kathleen |
P20Activity Code Description: To support planning for new programs, expansion or modification of existing resources, and feasibility studies to explore various approaches to the development of interdisciplinary programs that offer potential solutions to problems of special significance to the mission of the NIH. These exploratory studies may lead to specialized or comprehensive centers. |
A New Chinese Herb-Derived Selective Toll-Like Receptor Antagonist (Project 1) @ University of South Carolina At Columbia
Abstract: Atherosclerosis is the direct cause of heart attack and stroke, the No. 1 and No. 3 killers in the United States, respectively. It is the result of both lipid deposition and chronic vascular inflammation. Toll-like receptors (TLRs), the key components of innate immunity, play detrimental roles in every stage of atherosclerosis, with TLR2 and TLR4 being best documented. While participating in the first line of defense against invading pathogens, TLR2- and TLR4-mediated signaling is considered to be a driving force in atherogenesis. Thus, blockade of TLR2 and TLR4 signaling is an intriguing therapeutic approach for atherosclerosis. However, no TLR2 or TLR4 antagonists are currently approved for clinic use. Recently, in an effort to isolate and characterize single compounds from Sparganium stoloniferum tubers, a commonly used Traditional Chinese Medicine herb, we obtained a novel compound, designated Sparstolonin B (SsnB), and made exciting discoveries. Our preliminary studies show that 1) SsnB has potent anti-inflammatory effects on macrophages by selectively blocking TLR2 and TLR4 signaling; 2) SsnB diminishes the ability of activated endothelial cells to attract monocytes for adhesion, and decreases arterial smooth muscle cell migration; and 3) SsnB effectively suppresses inflammatory response to lipopolysaccharide (LPS) in mice. On the basis of these preliminary data, we hypothesize that SsnB can be developed as an anti-inflammatory and anti-atherogenic agent by virtue of its selective inhibitory effects on TLR2 and TLR4 signaling. To test this hypothesis, we propose three specific aims. SA1. To elucidate the molecular mechanism by which SsnB blocks TLR2 and TLR4 signaling. We will express and purify the Toll/IL-1 receptor (TIR) domains of TLRs, the adaptor proteins TIRAP/Mal and MyD88, and examine the binding of SsnB to these proteins. SA2. To examine the effects of SsnB on resident vascular cells. We will test the hypothesis that SsnB suppresses the inflammatory phenotype in arterial endothelial and smooth muscle cells by blocking TLR2 and TLR4 signaling. SA3. To test the hypothesis that SsnB attenuates atherogenesis in mice. LDL receptor (LDLR) deficient mice will be fed high fat diet to induce hypercholesterolemia and atherosclerosis. SsnB will be administrated to test if it attenuates atherogenesis in these mice. In summary, this study will test the anti-inflammatory and anti-atherogenic effects of a new natural compound recently isolated and characterized by us. The confirmation of the hypothesis that SsnB has anti-inflammatory and anti-atherogenic merit by blocking TLR2 and TLR4 signaling in macrophages and resident vascular cells will usher the development of this compound into an anti-atherogenic agent. This study will also provide a new example of complementary and alternative medicine bridging with modern pharmacology.
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0.946 |
2018 — 2021 |
Wood, Susan Kathleen |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Estrogen-Mediated Mechanisms of Stress Susceptibility @ University of South Carolina At Columbia
Project Summary Women are twice as likely as men to suffer from stress-related affective disorders, and as a result, are also at a greater risk of developing comorbid cardiovascular disease. This proposal investigates the estrogen (E)- mediated neural mechanisms that we suggest are initiated in the central amygdala (CeA) to promote innate stress vulnerability to both the emergence of negative valence and exaggerated cardiac sympathetic activation. The proposed series of studies relies on the use of a witness stress paradigm whereby a male or female rodent is located in a protected region of a dominant resident's cage and witnesses a social conflict between the resident and a smaller male intruder. Following stress exposure, females with either intact ovarian hormones, or ovariectomized with E replacement (OVX+E) exhibit negative valence (decreased sucrose preference, increased burying) and exaggerated cardiac sympathetic levels (elevated resting blood pressure) while OVX with vehicle replacement (OVX+V) and intact males are resilient, making this model ideal to study the role of estrogen on increased stress susceptibility. Aim 1 expands upon preliminary data that support the hypothesis that ovarian hormones, in particular E, exacerbate stress susceptibility. These studies will identify sex differences and estrogenic effects on behavioral and sympathetic indices of stress-related pathology. Aim 2 utilizes direct intra-CeA administration of an E receptor (ER) agonist (DPN) or antagonist (PHTPP), to activate or block, respectively, the ERs in the CeA. We hypothesize that inhibiting the ER in this brain region will enhance stress resiliency in the innate susceptible (intact-cycling) and induced susceptible (OVX+E) female groups, while activating the receptor will promote vulnerability in the induced resilient group (OVX). One known effect of E is its ability to increase the stress-related neuropeptide corticotropin-releasing factor (CRF), a peptide that is abundant in the CeA and is capable of inducing enhanced behavioral and sympathetic fear responses. Our data indicate that intact females exhibit increased CRF in the CeA, but only if they have a history of stress exposure. Therefore, Aim 2 will also identify if these ER treatments affect CRF expression in the CeA. Finally, Aim 3 will use virus-mediated gene transfer to reduce CRF levels in the CeA to determine whether the susceptibility-enhancing effects of the E are dependent upon CRF. Moreover, using in vivo microdialysis, studies in Aim 3 will identify whether increased CRF in the CeA has consequences on the major stress sensitive target the locus coeruleus (LC). CRF release and neuronal activity will be measured in the LC during stress/control and will identify if intact females exhibit increased CRF release in the LC and whether this translates to elevated activity. The ability of shRNA CRF knockdown in the CeA to affect LC activity and CRF release will also be assessed. Together, these studies will provide evidence of a targeted mechanism increasing susceptibility to affective disorders and comorbid cardiac dysfunction in females. These studies propose a novel and ?translatable? pathway by which E may regulate innate stress vulnerability in women.
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0.946 |