Richard A. Flavell

Bio: Richard A. Flavell is an academic researcher from Yale University. The author has contributed to research in topics: Immune system & T cell. The author has an hindex of 231, co-authored 1328 publications receiving 205119 citations. Previous affiliations of Richard A. Flavell include National Institute for Medical Research & University of Michigan.

The relationship of inflammation and initiation of autoimmune disease: role of TNF super family members.

Abstract: In normal people, autoreactive T cells can be deleted, either in the thymus or in the periphery, following presentation of self-peptides by host antigenpresenting cells (APCs) to self-reactive T cells (Kurts et al. 1996, 1998a,b). Breakdown in this putative tolerance mechanism is believed to contribute to autoimmunity in genetically susceptible individuals. Type I diabetes mellitus is characterized by infiltration of the islets of Langerhans by immune cells, which ultimately destroy the insulin-producing β-cells by T cellmediated mechanisms. The T cell-mediated nature of this autoimmunity requires that APCs not only have to present islet antigen released from β-cells but also have to deliver signals that promote survival of the self-reactive T cells. Identification of the cells and events that initiate and maintain this anti-islet inflammatory response is vital in the development of therapeutic strategies towards diabetes.

DNA Sequences Required for Regulated Expression of $\beta$ -Globin Genes in Murine Erythroleukaemia Cells

Abstract: We have introduced into murine erythroleukaemia (MEL) cells a series of human globin gene cosmids and two sets of hybrid genes constructed from the human beta-globin gene and the human gamma-globin or murine H-2Kbm1 genes. S1-nuclease analysis of the mRNA products from these genes before and after MEL cell differentiation showed that the human beta-globin gene, but not the human epsilon- or gamma-globin or H-2Kbm1 genes, is induced specifically. Hybrid genes containing human beta-globin DNA sequences from either 5' or 3' side of the translation initiation site were both inducible. Measurement of the relative rate of transcription showed this induction to be the result of transcriptional activation. We therefore suggest that DNA sequences which regulate beta-globin gene expression during MEL differentiation are located both 5' and 3' to the translation initiation site.

Isolation and characterization of a human collagen α 1(I)-like gene from a cosmid library

Abstract: We have isolated a human collagen alpha 1(I)-like gene from a cosmid library. The clone which contains 37kb of human DNA has been shown to contain this gene by DNA sequencing, hybrid arrest and hybrid selection assays and Northern blot hybridizations. The collagen gene sequence extends through most of the cloned DNA and must, therefore, be at least 35kb in length.

Executioner Caspase-3 and 7 Deficiency Reduces Myocyte Number in the Developing Mouse Heart.

Abstract: Executioner caspase-3 and -7 are proteases promoting cell death but non-apoptotic roles are being discovered. The heart expresses caspases only during development, suggesting they contribute to the organ maturation process. Therefore, we aimed at identifying novel functions of caspases in heart development. We induced simultaneous deletion of executioner caspase-3 and -7 in the mouse myocardium and studied its effects. Caspase knockout hearts are hypoplastic at birth, reaching normal weight progressively through myocyte hypertrophy. To identify the molecular pathways involved in these effects, we used microarray-based transcriptomics and multiplexed quantitative proteomics to compare wild type and executioner caspase-deficient myocardium at different developmental stages. Transcriptomics showed reduced expression of genes promoting DNA replication and cell cycle progression in the neonatal caspase-deficient heart suggesting reduced myocyte proliferation, and expression of non-cardiac isoforms of structural proteins in the adult null myocardium. Proteomics showed reduced abundance of proteins involved in oxidative phosphorylation accompanied by increased abundance of glycolytic enzymes underscoring retarded metabolic maturation of the caspase-null myocardium. Correlation between mRNA expression and protein abundance of relevant genes was confirmed, but transcriptomics and proteomics indentified complementary molecular pathways influenced by caspases in the developing heart. Forced expression of wild type or proteolytically inactive caspases in cultured cardiomyocytes induced expression of genes promoting cell division. The results reveal that executioner caspases can modulate heart’s cellularity and maturation during development, contributing novel information about caspase biology and heart development.

RIP2 contributes to Nod signaling but is not essential for T cell proliferation, T helper differentiation or TLR responses.

Abstract: Receptor-interacting protein 2 (RIP2), also known as CARDIAK and RICK, has been reported to play a role in both adaptive T cell responses and innate immunity as a mediator in TLR signaling and nucleotide-binding oligomerization domain (Nod) signaling. Because initial reports remain controversial, we have further examined both innate and adaptive immune responses in RIP2-deficient mice on the C57BL/6 background. Despite the up-regulation of RIP2 after T cell activation, we could not detect any defect in T cell proliferation or Th1/Th2 responses in RIP2-KO mice. Furthermore, we found that TLR responses in RIP2-deficient macrophages were normal. However, our analysis showed that Nod signaling was impaired in macrophages from RIP2-deficient mice. In conclusion, our data demonstrate a critical role for RIP2 in Nod signaling, while T cell proliferation, T helper differentiation and TLR responses were unaffected by the absence of RIP2.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei

Abstract: We have developed a procedure for preparing extracts from nuclei of human tissue culture cells that directs accurate transcription initiation in vitro from class II promoters. Conditions of extraction and assay have been optimized for maximum activity using the major late promoter of adenovirus 2. The extract also directs accurate transcription initiation from other adenovirus promoters and cellular promoters. The extract also directs accurate transcription initiation from class III promoters (tRNA and Ad 2 VA).

Apoptosis: A Review of Programmed Cell Death

Abstract: The process of programmed cell death, or apoptosis, is generally characterized by distinct morphological characteristics and energy-dependent biochemical mechanisms. Apoptosis is considered a vital component of various processes including normal cell turnover, proper development and functioning of the immune system, hormone-dependent atrophy, embryonic development and chemical-induced cell death. Inappropriate apoptosis (either too little or too much) is a factor in many human conditions including neurodegenerative diseases, ischemic damage, autoimmune disorders and many types of cancer. The ability to modulate the life or death of a cell is recognized for its immense therapeutic potential. Therefore, research continues to focus on the elucidation and analysis of the cell cycle machinery and signaling pathways that control cell cycle arrest and apoptosis. To that end, the field of apoptosis research has been moving forward at an alarmingly rapid rate. Although many of the key apoptotic proteins have been identified, the molecular mechanisms of action or inaction of these proteins remain to be elucidated. The goal of this review is to provide a general overview of current knowledge on the process of apoptosis including morphology, biochemistry, the role of apoptosis in health and disease, detection methods, as well as a discussion of potential alternative forms of apoptosis.