X-Git-Url: https://git.donarmstrong.com/?p=don.git;a=blobdiff_plain;f=resume%2Fresearch_statement.mdwn;h=397d4b6e97a2647b03d10a4c5c5eb6709ff66303;hp=0000000000000000000000000000000000000000;hb=5e1f47a06e05aea04f15a6145dd711af71d1d169;hpb=afd187e65eb57bfc98ab3adb6ec35b319b6d6e75 diff --git a/resume/research_statement.mdwn b/resume/research_statement.mdwn new file mode 100644 index 0000000..397d4b6 --- /dev/null +++ b/resume/research_statement.mdwn @@ -0,0 +1,225 @@ + + +# Research Objectives + +## Uncovering genetic causes of diseases using a multidisciplinary bioinformatics-driven approach + + + +My research focuses on designing and using bioinformatics techniques +to identify causes and mechanisms underlying human diseases such as +Systemic Lupus Erythematosus, Glioblastoma Multiforme, and +Arteriovenous Malformations followed be designing appropriate +diagnostics and treatment methods. Once identified, I work with +collaborators to verify the bioinformatics-discovered mechanisms +utilizing *in silico*, *in vitro*, and *in vivo* techniques, and +develop therapeutic and diagnostic techniques to identify and treat +the underlying human disorder. Cell-culture-based methods are utilized +as the first step in designing multi-target treatments, followed by +appropriate animal models.. + +# Unique Qualifications + +## Straddling Biology, Computer Science, and Statistics + +In addition to being a cellular and molecular biologist, I have +extensive experience in algorithm design, computer programming, and +statistics. The combination of these areas enables me to handle +biological problems which involve large numbers of samples and data +and require statistical analysis which can address confounders which +are often present in non-laboratory settings. It also gives me a +unique perspective which enables me to design novel methods to analyze +and interpret large amounts of data. + +## Multidisciplinary approach + +I have published in multiple disciplines, including membrane +biophysics, bioinformatics, genetics, and cellular biology. My +experiences in these fields and my experiences while transitioning +fields has allowed me to apply unique insights garnered from my +previous work to new topics leading to novel approaches and +breakthrough discoveries. + +# Previous Research Projects + + + +## Genetic Basis of System Lupus Erythematosus (SLE) + +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 +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. + +## Cancer Stem Cells in Glioblastoma + +Glioblastoma is a almost invariably fatal form of brain cancerwhich 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 +many chemotherapeutic agents. In collaboration with Florence Hoffman +at USC, I have classified glioblastoma-derived cancer stem cells and +cancer cell lines into distinct classes using gene microarrays and +various clustering approaches, which will enable the design of a +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}. + +# Future research directions + +## Identification of causal mutations in SLE + +While many regions and SNPs which are associated with SLE have been +identified, few of those regions have identified causal alleles with +known function. Furthermore, even for regions with identified causal +alleles, no systematic searches have been performed to identify +additional causal regions. Continuing my existing collaboration with +Chaim O. Jacob, I will rectify this by + +1. Deep sequencing the associated regions in 500 lupus cases and 1000 controls + +2. Identifying which newly found variants are associated with SLE + +3. Selecting variants with a high likelihood of producing functional variants + +4. Verifying biological relevance of variants by *in vitro* study + +5. Verifying functional relevance in human subjects + +## Developing analysis tools for massive amounts of sequencing data + +The ability to cheaply and rapidly sequence large numbers of samples +has massively increased the amount of data processing required by +researchers. Compounding this increase in data, most existing tools +have not been designed to take full advantage of the current advances +in computer architecture, which parallel solutions to problems which +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 + +1. Develop an open source massively parallel imputation method which + can combine existing GWAS results with new deep sequencing + and genetic profiling results. + +2. Extend same tools to call SNPs both incrementally and in parallel. + +I am currently working on extending samtools (an Open Source SNP +calling suite) to support running on multiple computers. + +## Gut microbiota alteration in SLE + +Many autoimmune disorders are known to be affected by gut microbiota. +Preliminary evidence suggests that mice which develop SLE have +differences in gut microbiota from mice which do not develop SLE, +which suggests that SLE severity may also be affected by differences +in human gut microbiota. I am currently developing novel methods to + +1. Determine which gut microbiota differ between mice with and + without SLE and using 16S sequencing + +2. Determine which gut microbiota differ between humans with and + without SLE using 16S sequencing, given #1. + +## Continuous, incremental analysis + +Just as science requires continuous testing of hypotheses, +bioinformatics is slowly moving towards continuous incremental +analysis of data. Most current tools use iterative analysis, where +analyses must be completely re-run with each new piece of data that is +obtained. When the amount of data remains small relative to the +overall computing power available, this is a feasible approach. +However, as the amount of data increases, it stops being feasible to +completely reanalyze data as new data is obtained, and incremental +analysis approaches are necessary. I will be working to extend +existing analysis pipelines to handle the incremental analysis of +data. + +# Research Funding + +## Funding Opportunities + +I anticipate obtaining funding from the following sources to pursue +the research goals outlined previously: + +1. National Institute of Health + + 1. [Research Project Grant (RO1)](http://grants.nih.gov/grants/guide/pa-files/PA-13-302.html) (NHGRI, NIAID, BISTI) + + 2. [NLM Career Development Award in Biomedical Informatics (K01)](http://grants.nih.gov/grants/guide/pa-files/PAR-13-284.html) + + 3. [Continued Development and Maintenance of Software (R01)](http://grants.nih.gov/grants/guide/pa-files/PAR-11-028.html) (extending existing biofinformatics software) + +2. Alliance for Lupus Research + + 1. [Target Identification in Lupus](http://www.lupusresearch.org/news-and-events/press-releases/til.html) + +3. Institution specific funding + +## Track Record of Funding + +The projects that I am proposing have a strong track record of being +funded by both the NIH and the Alliance for Lupus Research. + +# Wider impact of research agenda + + +My research will identify genetic variants and pathways underlying SLE +and other important human diseases, leading to better methodologies +for both the diagnosis and treatment of those diseases, and resulting +in significant decreases is patient morbidity and mortality. +Secondarily, the tools that I develop to effect this work will enable +researchers in other fields to more rapidly and cheaply identify +relevant factors for economically and environmentally important +phenotypes, such as pathogen-resistance in crops or +disease-susceptibility in thylocenes. Furthermore, as all of my tools +will be released under Open Source licenses, external researchers will +be able to build upon and improve my tools without being forced to +reinvent them. + + +\newpage + +\printbibliography +
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Only 4% of patients survive to 5 years after diagnosis

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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.

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and extending existing open source tools where they +exist

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