Ayyadevara, Srinivas, Ph.D.
  
Position title: Research Health Scientist, Central Arkansas Veterans Healthcare System     
Assistant Professor, Dept. of Geriatrics, University of Arkansas for Medical Sciences.
  
A. Personal Statement

 My primary interests, from the outset of my research career, have focused on basic mechanisms of aging, age-onset diseases, and the genetic and dietary regulation of lifespan. I have used model organisms for their facile genetics (chiefly C. elegans); and also studied human cells in culture in order to assess the potential for translation of nematode findings to humans. My research interests more recently extended to the protein aggregates and their effects on age-associated diseases, including atherosclerotic cardiovascular disease, sarcopenia and Alzheimer’s disease. I have extensive experience in proteomics, to identify proteins in aggregates and complex mixtures, and also to quantify protein abundances and analyze posttranslational modifications.

B. Positions and Honors
1988 - 3/1992           Junior Lecturer, Botany, Hyderabad, India
1992 – 1993             Graduate Teaching Assistant, Department of Chemistry, Louisiana Tech University, Ruston, Louisiana.
9/1999 – 3/2001       Instructor, Dept. of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR.
4/2002 – 3/2008       Research Assistant Professor, Donald W. Reynolds Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR.
11/2002 – present    Research Assistant Professor, Joint Appointment, Dept. of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR.
3/2008–10/2009       Research Scientist, Geriatrics Research, Education and Clinical Center (GRECC), Central Arkansas Veterans Healthcare Service, Little Rock, AR.
11/2009 – present    Research Scientist, Research Service, Central Arkansas Veterans Healthcare Service Little Rock, AR.
Other Experience and Professional Memberships
2012–present      Member, CAVHS Safety Committee
2010–present      Member, Editorial Board, International Journal of Methodology, Frontiers in Genetics

C. Contributions to Science
Signal transduction mediated by insulin and insulinlike growth factor: roles in aging and protein aggregation in Alzheimer’s and cardiovascular disease. Primary focus of my research as a VA Health Scientist has been the identification of novel proteomic biomarkers that are diagnostic or prognostic indicators of cardiovascular aging and disease, and of neurodegenerative diseases such as Alzheimer’s and Huntington diseases. This focus stems from a very fruitful collaboration with Drs. Griffin, Mehta and Reis and several skillful cardiothoracic surgeons, Drs. Moursi and Prayaga.  From this work, we identified numerous proteins in the compact aggregates of a Huntington’s model (Ayyadevara et al. 2015) and in Alzheimer’s cortex (2016) and also in hearts of aged and hypertensive mice (2016). My group utilizes a suite of techniques in these studies, including proteomics of human biopsies, immune­histochemistry, cell culture, proximity-ligation amplification, biochemical and proteomic approaches for analyses of protein complexes, and cutting-edge mass spectrometry for the analysis of aggregate proteins and their posttranslational modifications. I have focused on the molecular genetics of aging and insulin/IGF-1 signaling, wherein aberrant metabolic regulation can lead to disease states such as obesity, diabetes and cardiovascular disease.  I believe my laboratory is one of the few that can bring together gerontologists, proteomic experts, and both surgical and clinical cardiologists. The following manuscripts are directly relevant to my current research interests:
       
Ayyadevara S, Balasubramaniam M, Parcon PA, Barger SW, Griffin WS, Alla R, Tackett AJ, Mackintosh SG, Petricoin E, Zhou W, Shmookler Reis RJ.  Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls. Aging Cell. 2016 Oct;15(5):924-39

Ayyadevara S, Mercanti F, Wang X, Mackintosh SG, Tackett AJ, Prayaga SV, Romeo F, Shmookler Reis RJ, Mehta JL (2016). Age- and Hypertension-Associated Protein Aggregates in Mouse Heart Have Similar Proteomic Profiles. Hypertension. May;67(5):1006-1013. PMID:26975704. PMCID: PMC4833546.

Ayyadevara S, Balasubramaniam M, Gao Y, Yu Li-Rong, Zybaylov B, Alla R, and Shmookler reis RJ. (2015) Proteins in aggregates functionally impact multiple neurodegenerative disease models by forming proteasome-blocking complexes.  Aging Cell 14: 35-48. PMID: 25510159. PMCID: PMC4326912.

Bharill P, Ayyadevara S, Alla R, Shmookler Reis RJ. (2013)  Extreme depletion of PIP3 accompanies the increased life span and stress tolerance of PI3K-null C. elegans mutants. Front Genet.  4: 34. Epub 2013 Mar 28. PMID: 23543623

Development of novel genomic technologies to map quantitative trait loci affecting longevity.  As part of my graduate and postdoctoral research at the University of Arkansas for Medical Sciences, Dept. of Biochemistry and Molecular Biology (1993‒1999), I worked in the fields of quantitative genetics and gene mapping under the guidance of Dr. Robert Shmookler Reis.  My postdoctoral studies and subsequent research were influenced by interactive collaborations with the laboratories of Drs. Galecki and Jazwinski, resulting in 7 publications.  The purpose of the above research was to develop novel technologies to map genetic loci that help determine the longevity of C. elegans.  Ours was the first chromosome mapping of lifespan in any species, and later culminated in one of the first genes to be identified as a modulator of lifespan based on mapping studies, rec-8.  Subsequently, we showed that rec8 also affects yeast lifespan, and JP Magalhaes identified rec8 as one of 5 genes to undergo positive selection in the divergence of long-lived bowhead whales (200 y) from short-lived whale species (<55 y). 
Ayyadevara S,  Tazearslan C,  Alla R,  Jiang JC,  Jazwinski SM, Shmookler Reis RJ.  (2014)  Rec-8 dimorphism affects longevity, stress resistance and X-chromosome nondisjunction in C. elegans, and replicative lifespan in yeast.  Front. Genet. Genetics Aging 5:211. PMID: 25136348.
Shmookler Reis RJ, Kang P, and Ayyadevara S.  (2007)  Quantitative trait loci define genes and pathways by which longevity evolves.  Exper Gerontol  41:1046–1054. PMID: 1691941.
Ayyadevara S, Ayyadevara R, Vertino A, Galecki A, Thaden JJ, and Shmookler Reis RJ.  (2003) Quantitative trait loci affecting fitness and life span in Caenorhabditis elegans: Categorical trait interval mapping in CL2a × Bergerac-BO recombinant-Inbred worms.  Genetics 163: 557-570. PMID: 12618395
Ayyadevara S, Thaden JJ, and Shmookler Reis RJ.  (2000)  Anchor PCR Display: A high-throughput method to resolve, score and isolate dimorphic genetic markers based on interspersed repetitive DNA elements. Analyt Biochem  284: 19-28. PMID: 10933851.

Genetic interventions to extend life span:  A primary focus of my research has been the genetics of longevity and the development of tools to relieve age-related disorders. Although my training and much of my subsequent research has been conducted in close association with Dr. Robert Shmookler Reis, I have also entered into fruitful collaborations with several other investigators at CAVHS and UAMS, including Drs. Piotr Zimniak (CAVHS, UAMS) Jay Mehta (CAVHS, UAMS), and Kevin Raney (UAMS).  Representative publications in this area include:

Ayyadevara S, Alla R, Thaden JJ, Shmookler Reis RJ.  (2008)   Remarkable longevity and stress resistance of nematode PI3K-null mutants.  Aging Cell 7: 13–22. PMID: 17996009 (Selected by Faculty of 1000, 2008).

Shmookler Reis RJ, Xu L, Lee H, Chae M, Thaden JJ, Bharill P, Tazearslan C, Siegel E, Alla R, Zimniak P, Ayyadevara S. (2011)  Modulation of lipid biosynthesis contributes to stress resistance and longevity of C. elegans mutants.  Aging (Albany NY) 3:125-147. PMID: 21386131. PMCID: PMC3082008.

S Ayyadevara, Dandapat A, Singh SP, Benes H, Zimniak L, Reis RJ, Zimniak P. (2005)  Lifespan extension in hypomorphic daf-2 mutants of Caenorhabditis elegans is partially mediated by glutathione transferase CeGSTP2-2. Aging Cell  4:299-307. PMID: 16300482

S Ayyadevara, Engle MR, Singh SP, Dandapat A, Lichti CF, Benes H, Shmookler Reis RJ, Liebau E, Zimniak P.  (2005)  Lifespan and stress resistance of Caenorhabditis elegans are increased by expression of glutathione transferases capable of metabolizing the lipid peroxidation product 4- hydroxynonenal. Aging Cell 4:257-271. PMID:16164425.

Genetic and pharmacologic interventions to improve cardiovascular health: Largely through my interactions with Dr. Jay Mehta (CAVHS, UAMS), I have undertaken research on nematode and cell-culture models of cardiovascular diseases, and have used them to define pathways of action for aspirin and other pharmacologic interventions.
Ayyadevara S, Dandapat A, Bharill P, Hu CP, Khaidakov M, Mitra S, Shmookler Reis RJ, Mehta JL.  Aspirin inhibits oxidant stress, reduces aging-associated functional decline and prolongs lifespan of Caenorhabditis elegans. Antioxid Redox Signaling Jan 2013; 18, 481-490. PMID: 22866967

Mitra S, Khaidakov M, Lu J, Ayyadevara S, Szwedo J, Wang XW, Chen C, Khaidakov S, Kasula SR, Stone A, Pogribny I, Mehta JL. Prior exposure to oxidized low-density lipoprotein limits apoptosis in subsequent generations of endothelial cells by altering promoter methylation. Am J Physiol Heart Circ Physiol. 2011 Aug;301(2):H506-13. PMID: 21602467

c.    Khaidakov M, Szwedo J, Mitra S, Ayyadevara S, Dobretsov M, Mehta JL. (2010)  Anti-angiogenic and anti-mitotic effects of aspirin in hypoxia-reoxygenation: Modulation of LOX-1-NADPH oxidase axis as a potential mechanism. J Cardiovasc Pharmacol. 56:635–641. PMID: 20881612

Ayyadevara S, Mercanti F, Wang X, Mackintosh SG, Tackett AJ, Prayaga SV, Romeo F, Shmookler Reis RJ, Mehta JL (2016). Age- and Hypertension-Associated Protein Aggregates in Mouse Heart Have Similar Proteomic Profiles. Hypertension. May;67(5):1006-1013. PMID:26975704. PMCID: PMC4833546.

Over a decade of collaborative, inter-disciplinary research experience.  My long-term research goal is to explore the interface between aging, protein homeostasis, inflammation and development of cardio­vascular disease, and to make transformative and translatable discoveries in this area.  In addition to leading my independent research group, I also collaborate with numerous investigators on the VA and UAMS campuses. My group has expertise in aging, proteomics, cardiovascular aging and inflammation. We routinely use mass spectrometry to identify proteins in complex mixtures as well as to quantify protein abundances using various procedures (e.g., label-free, spectral counting, stable-isotope tags & SILAC). We have a PhD level bioinformaticist in the lab who supports our bench research with sophisticated molecular modeling. Collaborative work includes NIH grants as co-investigator, and over 25 publications.
Complete List of Published Work in My Bibliography (30 total publications):
http://www.ncbi.nlm.nih.gov/pubmed/?term=ayyadevara

D.  Research Support
Ongoing Support
VA Merit I01 BX001655                            RJ Shmookler Reis (P.I.)                   4/1/2013 – 8/31/2017 
      Mechanisms and Therapies for Age-Dependent Neurodegenerative Diseases         
      This proposal utilizes C. elegans to investigate the protein composition and modifications that contribute to age-dependent aggregation, using proteomic techniques and several models of neurodegeneration.  Those findings would then be tested for utility as indices of severity using banked human CNS autopsy samples.   
      Role: Co-Investigator

Completed Research Support (last 3 years):
1. Screening for Novel Drugs to Prevent and Treat Age-Related Sarcopenia.
Source:  Claude Pepper Older Americans Independence Center (OAIC) at UAMS
Period of support:  09/01/2015 – 08/30/2016
Role: Principal Investigator
Screen for novel pharmacologic agents that prevent or delay aggregation and/or age-dependent sarcopenia, in the nematode, C. elegans.

2.Role of amino-acid deficiency in aging-related muscle atrophy. 
      Source:  Claude Pepper Older Americans Independence Center (OAIC) at UAMS                                                                                                                             Period of support: 05/01/2012 – 04/30/2013
     Role: Principal Investigator
      The objective of this project is to identify amino acid levels in C. elegans longevity mutants preserving muscle mass with age which may help in understanding the etiology and treatment of skeletal muscle loss in mammalian system.
Range of variation in the duration of C. elegans dauer and post-dauer survival
      Source:  SENS Foundation                       Period of support: 04/01/2012 – 03/31/2013 (renewable)
      Role: Principal Investigator
      The objective of this project is to explore the role of dietary and environmental variables in determining the length of time dauer larvae can live and still resume the normal developmental and aging pathway.

E. Patents: US provisional patent, serial no. 60/894975 entitled “Methods for Identifying Modulators of Life Span and Resistance to Oxidative Stress”