Balasubramaniam,  Meenakshisundaram Ph.D.
  
Position title: Post Doctoral Fellow, Department of Geriatrics, University of Arkansas for Medical Sciences & Research & Development, Central Arkansas Veterans Health Service (WOC), Little Rock, Arkansas, USA.
   
A.  Personal Statement
            My primary research focus involves delineating the mechanisms behind age dependent protein aggregation and neurodegeneration. In order to understand the aggregate architecture and composition, I use various neurodegenerative model systems including C.elegans and human cell culture along with computational biology predictions. I got trained in C.elegans genetics and human cell cultures model systems by one of the world renowned pioneers in C.elegans aging research (Dr. Robert Reis & Dr. Srinivas Ayyadevara). I strongly believe, combining computational biology with molecular biology would set a wonderful platform for detailed understanding of any disease pathology and progression. So I pioneered a pipeline (workflow) that combines various computational biology techniques including protein structure modeling, molecular dynamics simulations & small molecular screening with wet lab biology including protein cross linking, proteomics, and gene specific knockdown in model systems and moderate throughput drug screening. This pipeline so far provided us some useful insights into understanding age dependent decline in protein homestasis and aggregation seen in Alzheimer's and Huntington's disease [1, 2, & 3].

Ayyadevara S, Balasubramaniam M, Gao Y, Yu L-R, Zybaylov B, Alla R, Shmookler Reis RJ (2015) Proteins in aggregates functionally impact multiple neurodegenerative disease models by forming proteasome-blocking complexes (First author). Aging Cell 14:35–48. PMC4326912. Featured in World Biomed. Frontiers, 2015.

Ayyadevara S, Balasubramaniam M, Parcon P, Barger SW, Griffin WS, Alla R, Tackett AJ, Mackintosh SG, Petricoin E, Zhou W, Shmookler Reis RJ(2016) Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer’s hippocampus from normal controls. Aging Cell 15: 924–939, 2016.  PMC5013017.

Ayyadevara S, Balasubramaniam M, Johnson J, Alla R, Mackintosh SG, Shmookler Reis RJ (2016) PIP3-binding proteins promote age-dependent protein aggregation and limit survival in C. elegans. Oncotarget7: 48870–48886. Cover article; selected as a Priority Research Paper.  DOI: 10.18632/oncotarget.10549

Parcon PA, Balasubramaniam M, Ayyadevara S, Jones RA, Shmookler Reis R, Barger SW, Mrak RE, Griffin WS.Apolipoprotein E4 inhibits autophagy through direct, specific binding to CLEAR motifs (First author manuscript under review Science)
  
B.  Awards
     Ranked 34 in University of Madras for Biochemistry Department (2005- 2008).
     Ranked 5thin University of Madras for Bioinformatics Department (2008-2010).
     Outstanding doctoral research award 2016 by EIT for UALR/UAMS joint bioinformatics program.

Veterans Administration Service
2012 - 2016 Graduate Research Assistant, without compensation (WOC)
2016-present Post doctoral fellow (WOC).

  
C. Contributions to Science
Identifying proteins that block protein degradation machinery in neurodegenerative diseases. From C.elegans Huntington’s disease model we isolated insoluble fractions and identified its protein composition through proteomics.  Based on prior knowledge about implications and human relevance, we chose few proteins for screening in C.elegans and found a novel protein that contributes to protein aggregation by blocking ubiquitin proteasome system. Gene specific knockdown rescues C.elegans from protein aggregation and associated traits.  Later on we named that protein as Cytotoxicity related aggregation mediator (CRAM-1).  Using protein structure modeling and molecular dynamics simulations we predicted the mechanism by which CRAM-1 blocks the protein degradation machinery [a]. Recently we found that, its ortholog in Human, SERF2 also mediates protein aggregation in human cell culture model Alzheimer's disease [b].   

a)Ayyadevara S, Balasubramaniam M, Gao Y, Yu L-R, Zybaylov B, Alla R, Shmookler Reis RJ (2015) Proteins in aggregates functionally impact multiple neurodegenerative disease models by forming proteasome-blocking complexes (First author). Aging Cell 14:35–48. PMC4326912. Featured in World Biomed. Frontiers, 2015 

b) Balasubramaniam M, Ayyadevara S, and ShmooklerReis R. Aggregate modulation of CRAM-1 by blocking UPS degradation and impact of SERF2 in Alzheimer's disease (Article ready for submission)

  
Identifying the dependence of PIP3 binding proteins in mediating protein aggregation and organism survival.  Protein aggregation and its associated toxicity is a process that involves many contributing factors.  Our lab holds the world record in longevity where Dr. Reis and Dr. Ayyadevara identified that PIP3 null mutants (C.elegans) lives almost 10 times longer than the wild type worms.  Recently we identified that knockdown of PIP3 binding proteins rescues worms from age dependent protein aggregation and increase lifespan.  Using proteomics approach we identified PIP3 and PIP2 binding proteins and with computational biology technique we identified the direct targets of PIP3 and knockdown of those proteins increased worm survival and decreased age associated traits [a]

a)Ayyadevara S, Balasubramaniam M, Johnson J, Alla R, Mackintosh SG, Shmookler Reis RJ. PIP3-binding proteins promote age-dependent protein aggregation and limit survival in C.elegans. Oncotarget 2016 Jul 12.
   
Allele specific involvement of APOE protein in Alzheimer's disease.
With a wonderful collaboration from Dr. Sue Griffin and her lab, we identified one of the possible mechanisms by which the presence of APOE4 allele increases the risk of onset of Alzheimer's disease. We performed the molecular biology and computational biology approach and identified that APOE4 binds specifically and directly to DNA (motif for autophagy gene expression) and reduces expression of autophagy which contributes to protein aggregation [a]

a)Parcon PA, Balasubramaniam M, Ayyadevara S, Jones RA, Shmookler Reis R, Barger SW, Mrak RE, Griffin WS.Apolipoprotein E4 inhibits autophagy through direct, specific binding to CLEAR motifs (First author manuscript under review Science)
  
Identification of Aspirin mediated effects on protein aggregation.  Using C.elegans and human cell culture models of neurodegeneration, we identified the protective roles of specific acetylations (through aspirin) that prevents protein phosphorylation and aggregation[a].

a)Ayyadevara S, Balasubramaniam M, AllaR, Mehta J.L,andShmooklerReisR. Aspirin-mediated acetylation protects against multiple neuropathies by reducing protein aggregation (first author article under review Antioxidant and Redox Signaling)  
  
Development of pipeline and scripts for automating various computational biology tools.  In order to speed up and reduce human bias in computational predictions especially in protein structure predictions and GROMACS simulations, I developed various automated scripts using Linux bash script and python.  We also developed our novel workflow/strategy for efficient drug discovery process.