2002 — 2006 |
Bansal, Meena B |
K08Activity Code Description: To provide the opportunity for promising medical scientists with demonstrated aptitude to develop into independent investigators, or for faculty members to pursue research aspects of categorical areas applicable to the awarding unit, and aid in filling the academic faculty gap in these shortage areas within health profession's institutions of the country. |
Il-6 Regulation of Matrix Degradation in Liver Fibrosis @ Mount Sinai School of Medicine of Nyu
DESCRIPTION (provided by applicant) Understanding mechanisms that favor regenerative rather than fibrotic responses is essential to developing strategies for treating and reversing chronic liver disease. This application addresses the central role played by interleukin-6 (IL-6) in determining this outcome through its effects on the activity of matrix degrading proteases in liver. IL-6-/-mouse livers exhibit increased injury, delayed wound healing, and fibrosis in models of acute and chronic toxin-induced injury, which correlates with increased matrix-metalloproteinase-2 (MMP-2) expression. Our data suggest that MMP-2 is profibrogenic, not only by hastening the replacement of the low density subendothelial matrix with a scar-like interstitial matrix rich in type I collagen, but also by its ability to degrade membrane type-1 matrix metalloproteinase (MT1-MMP), a potent type I collagenase. In addition, our results indicate that inappropriate downregulation of alpha2-macroglobulin, an IL-6 regulated gene, plays a critical role in increasing the net activity of MMP-2 in vivo and contributes to the increased injury and fibrosis in IL-6-/-livers. We hypothesize that IL-6 is a critical cytokine in the hepatic wound healing response by downregulating MMP-2 activity at the level of gene expression, activation of latent enzyme, and/or inhibition of active enzyme. The Specific Aims of this application are: (1) To characterize the level(s) at which IL-6 regulates MMP-2 expression and/or activation; (2) To determine whether increased activation of MMP-2 leads to decreased collagen type I degradation due to reduced levels/activity of MT1-MMP; (3) To assess the role of alpha2-macroglobulin in inhibiting MMP-2 in vivo; (4) To test the importance of MMP-2 in liver injury in vivo by administering MMP-2 inhibitors to IL6 +/+ and-/-mice with acute and chronic liver injury. These interrelated Specific Aims will be explored primarily using CC14 induced models of acute and chronic liver injury and primary stellate cell culture from IL-6+/+ and IL-6-/-livers. Immunoblot analysis, northern blot analysis, nuclear run-on assays, promoter analysis, gelatin zymography, and co-immunoprecipitation will be utilized to study specific aspects of these aims. In summary, the overall goal of this application is to elucidate the role of interleukin-6 in regulating liver injury and fibrosis via its effects on matrix degradation. Understanding these mechanisms will provide the basis for the development of novel anti-fibrotic therapies to treat a widely prevalent disease for which there is no effective treatment to date.
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2006 — 2007 |
Bansal, Meena B |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
Role of Matrix Metalloproteinase-2 in Liver Fibrosis @ Mount Sinai School of Medicine of Nyu
[unreadable] DESCRIPTION (provided by applicant): [unreadable] Regardless of the etiology of chronic liver injury, the final common pathway for liver injury and failure is fibrosis. Fibrosis with subsequent complications of portal hypertension results in the death of patients awaiting liver transplantation. Given the severe shortage of donor organs, there is an urgent need to understand the molecular basis of hepatic fibrosis in order to develop effective anti-fibrotic strategies. Liver fibrosis is characterized by activation of hepatic stellate cells which orchestrate a shift in the normal extracellular (ECM) comprised of mostly collagen type IV to a high-density interstitial matrix composed of predominantly type I collagen. Therefore, potential antifibrotic strategies include reduction in type I collagen synthesis, stimulation of matrix degradation, and/or promotion of stellate cell apoptosis. Matrix metalloproteinase-2 (MMP-2), a type IV collagenase, produced by activated hepatic stellate cells (HSCs), is increased in patients with chronic hepatitis and cirrhosis, suggesting a causative role in the fibrotic process. MMP-2 is also capable of acting as a type I collagenase, is upregulated in both animal and human hepatic fibrosis, is increased during resolution of fibrosis, and is associated with stellate cell apoptosis, we hypothesize that MMP-2 may play a protective rather than deleterious role in chronic liver injury. MMP-2 -/- mice offer an opportunity to clarify the physiologic role of MMP-2 in liver fibrosis. This study will employ the use of CCI4-induced chronic liver injury model to determine whether MMP-2 is important in attenuating liver fibrosis by directly reducing collagen I expression. Its role in acting as an interstitial collagenase will be assessed by 1) comparing the rate of spontaneous resolution of fibrosis between MMP-2 -/- and MMP-2 +/+ mice and 2) quantifying interstitial collagenase activity in both cohorts. In addition, a potential role for MMP-2 in promoting stellate cell apoptosis will be examined in both in vivo and in vitro models. Findings from these investigations may lead to novel approaches to the treatment of chronic fibrosing liver disease. [unreadable] [unreadable]
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2011 |
Bansal, Meena B |
R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
Stellate Cell-Hiv Interactions and Hepatic Fibrosis @ Icahn School of Medicine At Mount Sinai
HIV prevalence in the US is increasing due to a combination of the stable incidence of HIV (estimated at 53,600/cases year in 2006) and the longer life expectancy due to effective antiretroviral therapies. As HIV patients continue to live longer in the setting of effective ART, liver disease has become the leading cause of non-AIDS related mortality. Given the shortage of donor organs, the economic burden of transplant, and the aging cohort of HIV+ patients with underlying liver disease, there is an urgent need for the development of anti-fibrotic approaches for this population. This proposal focuses on understanding how HIV interacts with the activated hepatic stellate cell (HSC), which is thought to be a key cell responsible for fibrosis. Our long term goal is to determine how HIV accelerates fibrosis in all forms of liver disease through interactions with activated HSCs. The specific aims of the proposal are to: 1) Establish the pro-fibrogenic effects of HIV gp120 on HSCs in vitro and in vivo;2) Determine if HIV promotes TGFβ1 production by Kupffer cells (liver macrophages), which leads to paracrine stimulation of collagen I expression by activated HSCs;3) Examine if activated HSCs support HIV replication in vivo and/or transfer HIV to primary CD4+ T cells. Understanding how HIV accelerates liver fibrosis will lead to innovative anti-fibrotic approaches for HIV+ patients with underlying chronic liver injury. Reducing this burden of liver disease will substantially improve the health and survival of patients on long-term HAART and findings from this proposal will contribute knowledge important in achieving this goal.
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2015 — 2019 |
Bansal, Meena B |
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. |
Hiv and Hepatic Inflammation and Fibrosis @ Icahn School of Medicine At Mount Sinai
? DESCRIPTION (provided by applicant): HIV prevalence in the US is increasing due to a combination of the stable incidence of HIV (estimate at 53,600/cases year in 2006) and the longer life expectancy due to effective antiretroiral therapies (7). As HIV patients continue to live longer in the setting of effective ART, live disease has become the leading cause of nonAIDS related mortality (1). Because of shared routes of transmission, HCV and HBV are common in HIVinfected patients though other chronic liver diseases such as alcohol and fatty liver disease are also emerging.Epidemiologic data suggests that HIV accelerates liver fibrosis from a variety of liver diseases. Median time to cirrhosis in HIV/HCV coinfected patients is approximately 12 years sooner than HCV monoinfected patients(11,12). In the case of HIV/HBV coinfection, HIV/HBV coinfected patients are more than 8X likely to die from liver disease than those infected with HIV alone and 19X more likely to die from liver disease than HBV monoinfected individuals (14). In HIV monoinfected \ patients, NASH is emerging as a cause of liver disease. Given the shortage of donor organ, the economic burden of transplant (15), and the aging cohort of HIV + patients with underlying liver disease, there is an urgent need for the development of antifibotic treatments for this population. This application focuses on understanding how HIV interacts with 2 key cells in the liver which play an important in liver inflammation and fibrosis: 1) the activate hepatic stellate cell and 2) the liver macrophages (Kupffer cells). We will also examine if Kupffer cells are a reservoir for HIV in patients who are on antiretroviral therapies. Findings from this application will lead to innovative antifibrotic approaches for HIV + patients that may prevent the need for transplant and will advance our understanding of HIV reservoirs which is critical to finding a cure for HIV.
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