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Matthew K. Knabel

Bio: Matthew K. Knabel is an academic researcher from Johns Hopkins University. The author has contributed to research in topics: Gene knockdown & Liver transplantation. The author has an hindex of 4, co-authored 5 publications receiving 1084 citations.

Papers
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Journal ArticleDOI
27 May 2011-Cell
TL;DR: In this article, the pyruvate kinase isoforms PKM1 and PKM2 are alternatively spliced products of the PKM 2 gene, and they are activated by hypoxia-inducible factor 1 (HIF-1).

1,167 citations

Journal ArticleDOI
TL;DR: Whether pharmacologic mobilization of endogenous hematopoietic stem cells can aid in liver repair and improve survival in an animal model of ALF is investigated to suggest a possible new treatment strategy for patients with ALF.
Abstract: Objective:No therapy except liver transplantation currently exists for patients with acute liver failure (ALF). The aim of this study was to determine whether pharmacologic mobilization of endogenous hematopoietic stem cells (HSCs) can aid in liver repair and improve survival in an animal model of A

59 citations

Journal ArticleDOI
29 Apr 2015-PLOS ONE
TL;DR: It is demonstrated that delivery of miR-29 to the hepatic parenchyma using a clinically relevant gene delivery platform protects injured livers against fibrosis and suggests AAV-miR- 29 based therapies may be effective in treating a variety of fibroproliferative disorders.
Abstract: Fibrosis refers to the accumulation of excess extracellular matrix (ECM) components and represents a key feature of many chronic inflammatory diseases. Unfortunately, no currently available treatments specifically target this important pathogenic mechanism. MicroRNAs (miRNAs) are short, non-coding RNAs that post-transcriptionally repress target gene expression and the development of miRNA-based therapeutics is being actively pursued for a diverse array of diseases. Because a single miRNA can target multiple genes, often within the same pathway, variations in the level of individual miRNAs can potently influence disease phenotypes. Members of the miR-29 family, which include miR-29a, miR-29b and miR-29c, are strong inhibitors of ECM synthesis and fibrosis-associated decreases in miR-29 have been reported in multiple organs. We observed downregulation of miR-29a/b/c in fibrotic livers of carbon tetrachloride (CCl4) treated mice as well as in isolated human hepatocytes exposed to the pro-fibrotic cytokine TGF-β. Importantly, we demonstrate that a single systemic injection of a miR-29a expressing adeno-associated virus (AAV) can prevent and even reverse histologic and biochemical evidence of fibrosis despite continued exposure to CCl4. The observed therapeutic benefits were associated with AAV transduction of hepatocytes but not hepatic stellate cells, which are the main ECM producing cells in fibroproliferative liver diseases. Our data therefore demonstrate that delivery of miR-29 to the hepatic parenchyma using a clinically relevant gene delivery platform protects injured livers against fibrosis and, given the consistent fibrosis-associated downregulation of miR-29, suggests AAV-miR-29 based therapies may be effective in treating a variety of fibroproliferative disorders.

43 citations

Journal ArticleDOI
TL;DR: The ability to deliver anti-HCV short hairpin RNAs to uninfected livers before transplantation and subsequent exposure to HCV offers hope for the possibility of preventing the currently inevitable subsequent infection of liver grafts with HCV.
Abstract: Recurrent hepatitis C virus (HCV) infection is the most common cause of graft loss and patient death after transplantation for HCV cirrhosis. Transplant surgeons have access to uninfected explanted livers before transplantation and an opportunity to deliver RNA interference-based protective gene therapy to uninfected grafts. Conserved HCV sequences were used to design short interfering RNAs and test their ability to knockdown HCV transcript expression in an in vitro model, both by transfection and when delivered via an adeno-associated viral vector. In a rodent model of liver transplantation, portal venous perfusion of explanted grafts with an adeno-associated viral vector before transplantation produced detectable short hairpin RNA transcript expression after transplantation. The ability to deliver anti-HCV short hairpin RNAs to uninfected livers before transplantation and subsequent exposure to HCV offers hope for the possibility of preventing the currently inevitable subsequent infection of liver grafts with HCV.

6 citations

Dissertation
13 Dec 2013
TL;DR: .............................................................................................................................. ii Preface ............................................................................................... iv Table of
Abstract: .............................................................................................................................. ii Preface ............................................................................................................................... iv Table of

2 citations


Cited by
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Journal ArticleDOI
TL;DR: It is argued that altered metabolism has attained the status of a core hallmark of cancer.

2,623 citations

Journal ArticleDOI
03 Feb 2012-Cell
TL;DR: Oxygen homeostasis represents an organizing principle for understanding metazoan evolution, development, physiology, and pathobiology and rapid progress is being made in elucidating homeostatic roles of HIFs in many physiological systems, determining pathological consequences of H IF dysregulation in chronic diseases, and investigating potential targeting of Hifs for therapeutic purposes.

2,450 citations

Journal ArticleDOI
TL;DR: A brief refresher course on six of the major metabolic pathways involved in immunometabolism is provided, giving specific examples of how precise changes in the metabolites of these pathways shape the immune cell response.
Abstract: Immunometabolism is emerging an important area of immunological research, but for many immunologists the complexity of the field can be daunting. Here, the authors provide an overview of six key metabolic pathways that occur in immune cells and explain what is known (and what is still to be uncovered) concerning their effects on immune cell function. In recent years a substantial number of findings have been made in the area of immunometabolism, by which we mean the changes in intracellular metabolic pathways in immune cells that alter their function. Here, we provide a brief refresher course on six of the major metabolic pathways involved (specifically, glycolysis, the tricarboxylic acid (TCA) cycle, the pentose phosphate pathway, fatty acid oxidation, fatty acid synthesis and amino acid metabolism), giving specific examples of how precise changes in the metabolites of these pathways shape the immune cell response. What is emerging is a complex interplay between metabolic reprogramming and immunity, which is providing an extra dimension to our understanding of the immune system in health and disease.

1,857 citations

Journal ArticleDOI
TL;DR: Cancer cells then reprogramme adjacent stromal cells to optimize the cancer cell environment and activate out-of-context programmes that are important in development, stress response, wound healing and nutritional status.
Abstract: Contrary to conventional wisdom, functional mitochondria are essential for the cancer cell. Although mutations in mitochondrial genes are common in cancer cells, they do not inactivate mitochondrial energy metabolism but rather alter the mitochondrial bioenergetic and biosynthetic state. These states communicate with the nucleus through mitochondrial 'retrograde signalling' to modulate signal transduction pathways, transcriptional circuits and chromatin structure to meet the perceived mitochondrial and nuclear requirements of the cancer cell. Cancer cells then reprogramme adjacent stromal cells to optimize the cancer cell environment. These alterations activate out-of-context programmes that are important in development, stress response, wound healing and nutritional status.

1,709 citations

Journal ArticleDOI
TL;DR: Clinical trials can (and should) be initiated to test the hypothesis that incorporation of HIF inhibitors into current standard-of-care therapy will increase the survival of cancer patients.

1,281 citations