Kafatos:Povelones, Michael

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<font size="6" color="#ffffff">Laboratory of Immunogenomics</font><BR>&nbsp;<BR>
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[[Kafatos:Kafatos/Christophides Lab|Kafatos/Christophides Lab]]
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{{Kafatos/Christophides Lab}}
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<font size="5">'''Michael Povelones'''</font size>
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<font size="6" color="#555555">'''Michael Povelones'''</font>
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<font size="3" color="#ffffff">Division of Cell & Molecular Biology<br>[[image:Kafatos-white-mosquito.png|right]]
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Imperial College<br>
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<font size="3" color="#333333" class="mainfont">Division of Cell & Molecular Biology<br>
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Imperial College London<br>
South Kensington Campus<br>
South Kensington Campus<br>
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SAF Building<br>
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SAF Building, 6th Floor<br>
London, SW7 2AZ<br>
London, SW7 2AZ<br>
United Kingdom<br>
United Kingdom<br>
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[[Kafatos-pove-edu-prev-research|Education & Previous Research]]
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===Education===
 
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===Current Research Interests===
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<font class="mainfont">I am a postdoctoral fellow in the [[kafatos:Kafatos/Christophides Lab|Kafatos/Christophides lab]] at [http://www.imperial.ac.uk/ Imperial College London]. My research focuses on how the innate immune system of the mosquito recognizes and eliminates malaria parasites. Widely considered to be passive carriers of malaria, mosquitoes are actually amazing parasite killers. In fact, the vast majority of the parasites ingested when a mosquito bites a malarious person are attacked and eliminated before they can mount an infection. It is the few parasites that survive (even one is sufficient), that are ultimately responsible for disease transmission.
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* BA in Chemistry, [http://www.columbia.edu Columbia University], New York, NY, USA
 
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* PhD in Developmental Biology, [http://www.stanford.edu Stanford University], Stanford, CA, USA
 
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* Biology of Parasitism 2005, [http://www.mbl.edu MBL], Woods Hole, MA
 
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The mosquito has multiple lines of defense against invading pathogens, but the most potent is found in its blood, called hemolymph. Parasites migrate through the gut epithelium in order to escape the harsh digestive conditions of the gut lumen. Here they come into contact with the hemolymph. Two leucine-rich repeat (LRR) containing proteins, LRIM1 and APL1C, are essential for mosquito immune defense in this compartment. These proteins circulate in the mosquito hemolymph in a disulfide-bonded dimer (Povelones 2009). If either LRIM1 or APL1C is knocked-down by RNAi, the complex is undetectable in the hemolymph and parasite survival is massively increased. Before parasites are killed, the complement-like protein TEP1 is localized on their surface, marking them for destruction. The LRIM1/APL1C complex physically interacts with a proteolytically processed and highly reactive form of TEP1. The interaction stabilizes TEP1 in the hemolymph and is required for its localization to parasites during midgut invasion. When the LRIM1/APL1C complex is knocked-down, TEP1 fails to localize and the invading parasites are not killed. This immune pathway leading to parasite killing could be an important cause of natural refractoriness in non-vector mosquitoes (Habtewold, 2008). We recently discovered that the LRIM1/APL1C complex can also interact with 3 other members of the TEP family. Two of these were previously characterized to contribute to mosquito antibacterial defense reactions. We found that one of these, TEP3, also functions in mosquito immune reactions against parasites (Povelones, 2011). Understanding the mechanism of parasite killing, and how some parasites manage to escape, may open the door to novel control strategies.
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Additionally, we have found that LRIM1 and APL1C are defining members of a protein family, collectively named LRIMs (pronounced L-rims) (Povelones, 2009; Waterhouse 2010). Bioinformatic searches using specific features shared between LRIM1 and APL1C has uncovered approximately 20 family members falling into four distinct sub-families in the mosquito species ''Anopheles gambiae'', ''Aedes aegypti'' and ''Culex quinquefasciatus''. This family is not found in any other organism. Given the central role of LRR proteins in host defense in plants and animals, we are currently investigating the hypothesis that the repertoire of LRIMs may help the mosquito neutralize diverse pathogens, including the agents of human and animal diseases that they transmit. </font>
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===Current Research Interests===
 
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<font size="3">I am a postdoctoral fellow in the [[kafatos:Kafatos/Christophides Lab|Kafatos/Christophides Lab]] at [http://www.imperial.ac.uk/ Imperial College], London. Science is cool.</font>
 
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* [[pmid:19264986 | Povelones M, Waterhouse RM, Kafatos FC, Christophides GK. Leucine-Rich Repeat Protein Complex Activates Mosquito Complement in Defense Against Plasmodium Parasites. Science 2009 March 5 (Epub ahead of print)]]
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* [http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1002023 Povelones et al. Structure-Function Analysis of the Anopheles gambiae LRIM1/APL1C Complex and its Interaction with Complement C3-Like Protein TEP1. PLoS Pathogens (2011) vol. 7 (4) pp. e1002023]
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* [[pmid:18497855 |Habtewold T, Povelones M, Blagborough AM, Christophides GK. Transmission Blocking Immunity in the Malaria Non-Vector Mosquito ''Anopheles quadriannulatus'' Species A. PLoS Pathog. 2008 May 23;4(5).]]
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* [[pmid:20920294|Waterhouse et al. Sequence-structure-function relations of the mosquito leucine-rich repeat immune proteins. BMC Genomics (2010) vol. 11 pp. 531]]
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* [[pmid:19643026|Jaramillo-Gutierrez et al. Mosquito immune responses and compatibility between Plasmodium parasites and anopheline mosquitoes. BMC Microbiol (2009) vol. 9 pp. 154]]
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* [[pmid:19264986|Povelones et al. Leucine-rich repeat protein complex activates mosquito complement in defense against Plasmodium parasites. Science (2009) vol. 324 (5924) pp. 258-61]]
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* [[pmid:18497855|Habtewold et al. Transmission Blocking Immunity in the Malaria Non-Vector Mosquito Anopheles quadriannulatus Species A. PLoS Pathog (2008) vol. 4 (5) pp. e1000070]]
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===Previous Research===
 
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<font size="3">I received my doctoral degree at [http://www.stanford.edu Stanford University] in the laboratory of [http://www.stanford.edu/~rnusse/ Roel Nusse]. The focus of my research was understanding how the ''frizzled (fz)'' receptor in ''Drosophila'' functions in planar cell polarization (PCP) and Wnt-mediated cell fate specification. ''fz'' controls two different signal transduction pathways for each of these distinct developmental outcomes. How does a single receptor function in two signaling pathways? This work revealed that even though cell fate signaling requires a Wnt ligand, ''fz'' is not activated by any of the 7 ''Drosophila'' Wnt genes for its PCP function. Instead, ''fz'' has an intrinsic ability to control components of the PCP pathway and that it associates with pathway specific Wnt co-receptor for cell fate signaling. In addition, a structure-function analysis of ''fz'' suggested that, in addition to the Wnt binding site located in the extracellular cysteine-rich domain, there is a second Wnt-binding site within the transmembrane portion of the receptor.</font>
 
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[[Image:Kafatos-pove-fz.png|right|220px]]
 
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* [[pmid:16163385|Povelones M and Nusse R. The role of the cysteine-rich domain of Frizzled in Wingless-Armadillo signaling. EMBO J 2005 Oct 5; 24(19) 3493-503.]]
 
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* [[pmid:16085697|Povelones M, Howes R, Fish M, and Nusse R. Genetic evidence that Drosophila frizzled controls planar cell polarity and Armadillo signaling by a common mechanism. Genetics 2005 Dec; 171(4) 1643-54.]]
 
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* [[pmid:12415278|Povelones M and Nusse R. Wnt signalling sees spots. Nat Cell Biol 2002 Nov; 4(11) E249-50.]]
 
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* [[pmid: 18555784|Chen WS, Antic D, Matis M, Logan CY, Povelones M, Anderson GA, Nusse R, Axelrod JD. Asymmetric homotypic interactions of the atypical cadherin flamingo mediate intercellular polarity signaling. Cell. 2008 Jun 13;133(6):1093-105.]]
 
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<font size="3">I worked in the laboratory of [http://www.cumc.columbia.edu/dept/gsas/anatomy/Faculty/Ambron/index.html Richard Ambron] as an undergraduate and research technician at [http://www.columbia.edu Columbia University]. The focus of this research was the identification of intrinsic nerve injury signals. In addition to growth factor and electrophysiological responses, neurons posses axonal proteins with a masked nuclear localization sequence (NLS) that serve as a sensor for injury. These injury signals are activated and rapidly retrogradely transported to the neuronal cell body and into the nucleus following nerve crush injury. In the nucleus they function to initiate the transcriptional program for repair. My research focused on the identification of an NF-&kappa;B-like transcription factor in Aplysia and its function in nerve injury. Nerve regeneration following injury requires transcriptional activation of repair genes. Members NF-&kappa;B family of transcription factors are well-suited to play a role in nerve injury since they contain and masked NLS and are localized to the cytoplasm until activated. This work identified by electrophoretic mobility shift assay an NF-&kappa;B-like activity in axoplasm. Contrary to what was expected, this activity was rapidly inactivated in injured neurons. We hypothesized that in these neurons, NF-&kappa;B functions as a signal of homeostasis and must be inactivated following injury since it regulates genes that are incompatible with repair. </font>
 
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[[Image:kafatos-injured-neuron.png|right]]
 
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* [[pmid:11257614|Sung YJ, Povelones M, and Ambron RT. RISK-1: a novel MAPK homologue in axoplasm that is activated and retrogradely transported after nerve injury. J Neurobiol 2001 Apr; 47(1) 67-79.]]
 
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* [[pmid:11153011|Farr M, Zhu DF, Povelones M, Valcich D, and Ambron RT. Direct interactions between immunocytes and neurons after axotomy in Aplysia. J Neurobiol 2001 Feb 5; 46(2) 89-96.]]
 
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* [[pmid:9185529|Povelones M, Tran K, Thanos D, and Ambron RT. An NF-kappaB-like transcription factor in axoplasm is rapidly inactivated after nerve injury in Aplysia. J Neurosci 1997 Jul 1; 17(13) 4915-20.]]
 
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* [[pmid:8922402|Ambron RT, Zhang XP, Gunstream JD, Povelones M, and Walters ET. Intrinsic injury signals enhance growth, survival, and excitability of Aplysia neurons. J Neurosci 1996 Dec 1; 16(23) 7469-77.]]
 
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Revision as of 12:38, 2 May 2011

Laboratory of Immunogenomics
 
Kafatos/Christophides Lab


Michael Povelones

Division of Cell & Molecular Biology
Imperial College London
South Kensington Campus
SAF Building, 6th Floor
London, SW7 2AZ
United Kingdom
Image:Kafatos-pove-email.png

Education & Previous Research


Current Research Interests

I am a postdoctoral fellow in the Kafatos/Christophides lab at Imperial College London. My research focuses on how the innate immune system of the mosquito recognizes and eliminates malaria parasites. Widely considered to be passive carriers of malaria, mosquitoes are actually amazing parasite killers. In fact, the vast majority of the parasites ingested when a mosquito bites a malarious person are attacked and eliminated before they can mount an infection. It is the few parasites that survive (even one is sufficient), that are ultimately responsible for disease transmission.


The mosquito has multiple lines of defense against invading pathogens, but the most potent is found in its blood, called hemolymph. Parasites migrate through the gut epithelium in order to escape the harsh digestive conditions of the gut lumen. Here they come into contact with the hemolymph. Two leucine-rich repeat (LRR) containing proteins, LRIM1 and APL1C, are essential for mosquito immune defense in this compartment. These proteins circulate in the mosquito hemolymph in a disulfide-bonded dimer (Povelones 2009). If either LRIM1 or APL1C is knocked-down by RNAi, the complex is undetectable in the hemolymph and parasite survival is massively increased. Before parasites are killed, the complement-like protein TEP1 is localized on their surface, marking them for destruction. The LRIM1/APL1C complex physically interacts with a proteolytically processed and highly reactive form of TEP1. The interaction stabilizes TEP1 in the hemolymph and is required for its localization to parasites during midgut invasion. When the LRIM1/APL1C complex is knocked-down, TEP1 fails to localize and the invading parasites are not killed. This immune pathway leading to parasite killing could be an important cause of natural refractoriness in non-vector mosquitoes (Habtewold, 2008). We recently discovered that the LRIM1/APL1C complex can also interact with 3 other members of the TEP family. Two of these were previously characterized to contribute to mosquito antibacterial defense reactions. We found that one of these, TEP3, also functions in mosquito immune reactions against parasites (Povelones, 2011). Understanding the mechanism of parasite killing, and how some parasites manage to escape, may open the door to novel control strategies.


Additionally, we have found that LRIM1 and APL1C are defining members of a protein family, collectively named LRIMs (pronounced L-rims) (Povelones, 2009; Waterhouse 2010). Bioinformatic searches using specific features shared between LRIM1 and APL1C has uncovered approximately 20 family members falling into four distinct sub-families in the mosquito species Anopheles gambiae, Aedes aegypti and Culex quinquefasciatus. This family is not found in any other organism. Given the central role of LRR proteins in host defense in plants and animals, we are currently investigating the hypothesis that the repertoire of LRIMs may help the mosquito neutralize diverse pathogens, including the agents of human and animal diseases that they transmit.



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