X-Git-Url: https://git.donarmstrong.com/?p=don.git;a=blobdiff_plain;f=resume%2Fresearch_statement.mdwn;h=70283a36fa30367b785085ae36eae4334e8b2fe4;hp=397d4b6e97a2647b03d10a4c5c5eb6709ff66303;hb=0d1dd69a06708c933c86844fa9b49ca79cabddcc;hpb=5e1f47a06e05aea04f15a6145dd711af71d1d169 diff --git a/resume/research_statement.mdwn b/resume/research_statement.mdwn index 397d4b6..70283a3 100644 --- a/resume/research_statement.mdwn +++ b/resume/research_statement.mdwn @@ -51,22 +51,22 @@ I developed novel bioinformatic methods which increase likelihood of identifying reproducible genetic associations using prior knowledge from publicly available databases and expert -information \cite{Armstrong2008:function2gene}. Using these methods, I -was able to identify genes previously unassociated with SLE in a -trio-based study \cite{Jacob2007:ar_lupus}. These genes were then +information [#Armstrong2008:function2gene]. Using these methods, I was +able to identify genes previously unassociated with SLE in a +trio-based study [#Jacob2007:ar_lupus]. These genes were then replicated in a larger case-control study which was funded by the NIH -on the basis of the original findings -\cite{Jacob2009:sle_irak1,Armstrong2009:sle_gi}. Among other findings, -this larger study identified a missense allele in NCF2 (H389Q, -rs17849502) which was associated with SLE. Collaborative work -indicated that H389Q altered the binding energy of NCF2 with VAV1 -using docking simulations, and in vitro experiments confirmed that -H389Q altered NADPH oxidase function \cite{Jacob2012:sle_ncf2}, thus -identifying it as a causative SLE mutation. +on the basis of the original findings [#Jacob2009:sle_irak1] , +[#Armstrong2009:sle_gi]. Among other findings, this larger study +identified a missense allele in NCF2 (H389Q, rs17849502) which was +associated with SLE. Collaborative work indicated that H389Q altered +the binding energy of NCF2 with VAV1 using docking simulations, and in +vitro experiments confirmed that H389Q altered NADPH oxidase function +[#Jacob2012:sle_ncf2], thus identifying it as a causative SLE +mutation. ## Cancer Stem Cells in Glioblastoma -Glioblastoma is a almost invariably fatal form of brain cancerwhich is +Glioblastoma is a almost invariably fatal form of brain cancer[^survival_rate] which is diagnosed in \(\approx\) 9,000 people in the US annually. It is typified by high levels of chemotherapeutic-resistant recurrences, some of which is likely caused by cancer stem cells which are insensitive to @@ -79,14 +79,14 @@ class-specific treatment of this devastating disease. ## Regulatory pathways underlying cranial arteriovenous malformations The mechanisms underlying the formation of arteriovenous -malformations(AVMs) which -occur in the brain are unknown. Using gene microarrays, qtPCR, and *in -vitro* experiments on primary human endothelial cells cultured from -resected AVMs, I indentified multiple gene regulation pathways, many -of them novel, including the Id1/Thsb1 inhibitory pathway. Additional -experiments indicated that the *in vitro* pathology of endothelial -cells could be partially rescued using extracellular Thsb1 -\cite{Stapleton2011:thbs1}. +malformations[^avm_definition] (AVMs) which occur in the brain are +unknown. Using gene microarrays, qtPCR, and *in vitro* experiments on +primary human endothelial cells cultured from resected AVMs, I +indentified multiple gene regulation pathways, many of them novel, +including the Id1/Thsb1 inhibitory pathway. Additional experiments +indicated that the *in vitro* pathology of endothelial cells could be +partially rescued using extracellular Thsb1 +[#Stapleton2011:thbs1]. # Future research directions @@ -120,9 +120,9 @@ can be run on architectures with vastly differing computational abilities (such as GPUs). To resolve this, I am in the process of actively developing new open -source tools which are capable of running on massively parallel -architectures using both multiple computers (openMPI) and multiple -GPUs on the same computer (Nvidia's CUDA) to +source tools[^extending_note] which are capable of running on +massively parallel architectures using both multiple computers +(openMPI) and multiple GPUs on the same computer (Nvidia's CUDA) to 1. Develop an open source massively parallel imputation method which can combine existing GWAS results with new deep sequencing @@ -204,22 +204,41 @@ be able to build upon and improve my tools without being forced to reinvent them. -\newpage +[#Armstrong2009:sle_gi]: D L Armstrong et al. “Identification of new SLE-associated genes with a two-step + Bayesian study design”. In: Genes Immun. 10.5 (July 2009), pp. 446–456. doi: + [10.1038/gene.2009.38](http://dx.doi.org/10.1038/gene.2009.38). + +[#Armstrong2008:function2gene]: Don L Armstrong, Chaim O Jacob, and Raphael Zidovetzki. “Function2Gene: a + gene selection tool to increase the power of genetic association studies by utilizing + public databases and expert knowledge”. In: BMC Bioinformatics 9 (2008), p. 311. + doi: [10.1186/1471-2105-9-311](http://dx.doi.org/10.1186/1471-2105-9-311). + +[#Jacob2009:sle_irak1]: Chaim O Jacob et al. “Identification of IRAK1 as a risk gene with critical role + in the pathogenesis of systemic lupus erythematosus”. In: Proc. Natl. Acad. Sci. + U.S.A. 106.15 (Apr. 2009), pp. 6256–6261. doi: [10.1073/pnas.0901181106](http://dx.doi.org/10.1073/pnas.0901181106). + +[#Jacob2007:ar_lupus]: Chaim O Jacob et al. “Identification of novel susceptibility genes in childhood- + onset systemic lupus erythematosus using a uniquely designed candidate gene + pathway platform”. In: Arthritis Rheum. 56.12 (Dec. 2007), pp. 4164–4173. doi: + [10.1002/art.23060](http://dx.doi.org/10.1002/art.23060). -\printbibliography -
-

Footnotes:

-
+[#Jacob2012:sle_ncf2]: Chaim O Jacob et al. “Lupus-associated causal mutation in neutrophil cytosolic + factor 2 (NCF2) brings unique insights to the structure and function of NADPH + oxidase”. In: Proc. Natl. Acad. Sci. U.S.A. 109.2 (Jan. 2012), pp. 59–67. doi: + [10.1073/pnas.1113251108](http://dx.doi.org/10.1073/pnas.1113251108). -
1

Only 4% of patients survive to 5 years after diagnosis

+[#Stapleton2011:thbs1]: Christopher J Stapleton et al. + “Thrombospondin-1 modulates the angiogenic phe- notype of human + cerebral arteriovenous malformation endothelial cells”. In: + Neurosurgery 68.5 (May 2011), pp. 1342–1353. + doi: [10.1227/NEU.0b013e31820c0a68](http://dx.doi.org/10.1227/NEU.0b013e31820c0a68). -
2

Direct artery to vein connection without an -intervening capilary bed; leads to high pressure arterial flow in -venous tissue and can lead to hemmorrhage and death.

+[survival_rate]: Only 4% of patients survive to 5 years after diagnosis -
3

and extending existing open source tools where they -exist

+[avm_definition]: Direct artery to vein connection without an + intervening capilary bed; leads to high pressure arterial flow in + venous tissue and can lead to hemmorrhage and death. +[extending_note]: and extending existing open source tools where they + exist -
-
\ No newline at end of file