Shmookler Reis,  Robert Joseph, D.Phil.

Position titles: Professor and Udupa Chair in Geriatrics, Reynolds Institute on Aging/Dept. of Geriatrics; Professor of Biochemistry/Molecular Biology and Pharmacology/Toxicology, Univ. of Arkansas for Medical Sciences; Senior Research Career Scientist, Central Arkansas Veterans Healthcare System. Little Rock AR.
  
A. Personal Statement

     My research career has focused on the molecular genetics of longevity and age-associated diseases, using both previously defined mutations and gene mapping combined with bioinformatics approaches.  I was trained in Drosophila and mammalian genetics, adding C. elegans in 1989 as a model system in which to develop QTL mapping and thus to define genes that modulate longevity.  In mammalian genetics, we were the first to identify the Pirin gene on the X chromosome as a determinant of post-menopausal bone loss in women, a discovery subsequently confirmed in a Chinese population. We also pioneered studies of homologous recombination (HR) and its roles in the etiology and subsequent progression of myeloma, prostate and breast cancers.  Data from our laboratory, and subsequently many others, support the hypothesis that HR generates genetic diversity from which more highly oncogenic clones emerge by cell selection.  We have focused recently on protein aggregation as a unifying feature of many or all age-dependent diseases [1–4] and on specific aggregate proteins that appear to play functional roles in the formation or clearance of aggregates. We use proteomics to identify proteins in aggregates of human neurodegenerative diseases; their known or predicted structures allow molecular-dynamic simulations of protein-protein and protein-drug interactions. Predictions from in silico studies are then tested in vivo in models of Alzheimer’s and other human neurodegenerative diseases [1,2]. Molecular genetics and bioinformatics provide complementary tools to discover and exploit causal links.
   1. Ayyadevara S, Balasubramaniam MS, Gao Y, Yu LR, Zybaylov B, Alla R, Shmookler Reis RJ (2015) Proteins in
   aggregates functionally impact multiple neurodegenerative disease models by forming proteasome-blocking
   complexes. Aging Cell 14:35–48. PMC4326912.  Featured in World Biomed. Frontiers, 2015.
   2. 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.
   3. Ayyadevara S, Mercanti F,  Wang XW, Mackintosh SG, Tackett AJ, Prayaga VS, Romeo F, Shmookler Reis RJ,
   Mehta JL (2016) Age- and hypertension-associated protein aggregates in mouse heart have similar proteomic
   profiles. Hypertension 67:1006–1013. PMID: 26975704.
   4. 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.  Oncotarget 7: 
   48870–48886.  Cover article; selected as a Priority Research Paper.  DOI: 10.18632/oncotarget.10549

B. Positions and Honors

1977–1980        MRC Professional Associate, McMaster University Medical Centre, Hamilton, Ontario, Canada
1980–1983         Assist. Professor, Depts. of Medicine & Biochemistry, Univ. of Arkansas for Medical Sciences
1983–1992        Assoc. Professor, Depts. of Medicine, Biochemistry/Molecular Biology and Pharmacology, UAMS
1984–2002        Research Scientist, GRECC, Central Arkansas Veterans Healthcare System, Little Rock, AR
2003–2013        Research Career Scientist, Central Arkansas Veterans Healthcare System, Little Rock, AR
1992–present    Professor, Depts. of Geriatrics, Biochemistry & Molecular Biology, and Pharmacology, UAMS
2002–present   Udupa Chair of Gerontologic Research, University of Arkansas for Medical Sciences
   2013–present   Sr. Research Career Scientist, Central Arkansas Veterans Healthcare System, Little Rock, AR
 Offices held and committee service in national/international professional organizations
 1985-1987      Member, NIA Genetics and Molecular Biology Advisory Council
           1985      Co-Convener of Special Session: “Molecular Instability and Aging”, International Aging 
                                     Association/American Aging Association Annual Meeting, New York, NY
           1988      Co‑organizer, Symposium on "Molecular Biology of Aging", American Aging Association 18th  
                                      Annual Meeting, San Antonio, TX
           1989      Organizer and chairman, three Symposia on "The Hayflick Model of Senescence",  
                                      Gerontological Soc. of America 42nd Annual Meeting, Minneapolis MN.
           1990      Co‑organizer/chairman, 3 Symposia on “Cellular Aging", Gerontol. Soc. of America, Boston MA.
           1993      Chairman, "Genetics of Aging" Symp., Keystone Symp. on Molec. Biol. of Aging, Lake Tahoe, CA.
           1996      Chairman of Session, Cellular Aging. Gerontol. Soc. Amer. 49th Ann. Mtg., Washington DC.
2003–2006      International Workshops, Genetics of Bone Disease. Organizing Committee. Davos, Switzerland.
2012, 2014      Chairman of Program Committee; Session Chair, Damage-Control Mechanisms in Longevity;   
                                2nd & 3rd International Conferences on Genetics of Aging and Longevity, Moscow, Russia.
          2014      Chair, Session on Longevity Genes, Cold Spring Harbor Symposium, Molec. Genetics of Aging.

Membership on national grant proposal review boards
1983-present  Member, Grant Review/Site Visit Teams for NIH (25), Dept. of Energy and NCI
1984-1988       Member, NIH Molecular Cytology Study Section
1986                 Chairman, NIA Scientific Merit Review Committee
1987                 Chairman, NIA Program Project Site Visit Team/Review Committee
1987                 Chairman, Biomarkers Study Section B, NIA Gerontology–Geriatrics Review Committee
1988-1992       Member, NIH Reviewers Reserve
2000-2003       Member, Veterans Admin. Merit Review Advisory Group, & Career Dev’t Review Committee
2006                 Chairman, NIH/CSR Special Emphasis Panel, ZRG1-BDA-A
2008                 Member, Site Visit Team, NIH/NICHHD Intramural Prog., Differentiation Genetics (I. Dawid)
2009-2010       Member, Veterans Administration Career Development Review Committee
2011                 Chairman, NIH/NIA Special Review Board (ZAG1 ZIJ-1)
2013                 Member/Chair, NIH/NIA Special Review Board (ZAG1 ZIJ-2) 10/28/2013.
2014                 Member, VA Merit Review Board, Neurodegenerative Diseases, Veterans Administration Service
1991 – 2001    Chairman, Little Rock VAMC Safety and Recombinant DNA Biosafety Committee
2000–2003      Member, MRAG & CaDe Review Committee, U.S. Dept. of Veterans Affairs
2009 – 2010    Member, Career Development Review Committee, U.S. Dept. of Veterans Affairs
2010–present Member, CAVHS Research & Development Committee
2015–present Chair, Central Arkansas Veterans Healthcare Service, Research & Development Committee

C.  Contributions to Science

1. Development and application of gene-mapping to identify quantitative trait loci (QTLs) affecting longevity and age-dependent diseases. At a time when QTL mapping was first being developed and had been applied only in plant genetics, we developed novel protocols and algorithms [e.g., 1a] to map genetic loci that influence the longevity of the nematode 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 [1b, 1c]. Subsequently, we showed that rec8 also affects yeast lifespan [1c], and J.P. Magalhaes identified rec8 as one of 6 genes to undergo positive selection as long-lived bow­head whales (lifespan >200 y) diverged from shorter-lived whale species (lifespans <55 y).  In mammalian genetics, we were among the first to undertake QTL mapping to define mouse loci that contribute to bone density and age-dependent osteopenia.  Translating mouse QTL data to human SNP mapping, we identified the Pirin gene on the X chromosome as a determinant of post-menopausal bone loss in women [1d], a discovery subsequently confirmed in a Chinese population. 
   1a. Ayyadevara S, Ayyadevara R, Vertino A, Galecki A, Thaden JJ, 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. 12618395
  ​ 1b. Vertino A, Ayyadevara S, Thaden JJ, Shmookler Reis RJ. (2011)  A narrow quantitative trait locus in C.
   elegans coordinately affects longevity, thermotolerance, and resistance to paraquat. Front Genet 2: Art.63.
   PCMID: PMC3268616.
  ​ 1c. 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. 5:211. PCMID: PMC4120681.
  ​ 1d. Parsons CA, Mroczkowski HJ, McGuigan FE, Albagha OM, Manolagas S, Reid DM, Ralston SH, Shmookler
   Reis RJ.  (2006)  Interspecies synteny mapping identifies a quantitative trait locus for bone mineral density on
   human chromosome Xp22.  Hum Mol Genet 14: 3141–3148. 16183656

​2. Studies of isogenic longevity mutants to define biomarkers and mechanisms of lifespan control. We outcrossed 12 mutants that had been reported as long-lived in the literature, into a constant genetic back­ground – the relatively long-lived N2-DRM control strain. Lifespans of these isogenic strains and the control/ back­ground strain revealed several mutants that were substantially less long-lived than reported, and three mutants that exceeded their published lifespans. The daf-2(e1370) strain, discovered by the Kenyon group to live 1.9x the wild-type lifespan, consistently survived 2.3-fold longer than N2-DRM.  Both age-1(mg44) and age-1(m333), reported to live 2- to 2.3-fold longer than controls, actually lived 9- to 11-fold longer – the greatest life extension found for any mutant in any species [2a]. The mutant panel enabled us to discover biomarkers that correlate with lifespan [2a‒2c, 5c] rather than with age. Transcript-level markers revealed that many nutrient- and stress-signaling pathways are silenced in exceptionally long-lived lines [2b, 2d]. Metabolomic studies implicated fatty acids as critical determinants of longevity, with strain longevity inversely correlated with PUFA content and FA chain length, but positively correlated to MUFA content [2c] – paralleling studies in which similar changes were seen in erythrocyte lipids from children of nonagenarians, relative to controls with parents of unexcep­tional longevity [Puca et al., Rejuv Res 11: 63–72, 2008].
   2a. 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. PMC1819584 (Selected by Faculty of 1000, 2008)
   2b. Tazearslan C, Ayyadevara S, Bharill P, Shmookler Reis RJ (2009) Positive feedback between transcriptional
   and kinase suppression confers extraordinary longevity and stress resistance.  PLoS Genetics, 5: e1000452.
   PMC2661368.
  ​ 2c. 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.  PMC3082008
  ​ 2d. 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. Frontiers Genet 4: 34.  PMC3610087
 
​3. Homologous recombination creates most genetic variation that fuels initiation, progression and drug resistance of diverse cancers.  We were the first to document that immortal cell lines, including 5 different cancer types, have markedly elevated levels of homologous recombination (HR), and similar elevation of Rad51 transcripts encoding the human recombinase [3a].  HR generates genetic diversity from which increasingly oncogenic clones emerge by cell selection, driving cancer initiation and progression [3b].  We have focused recently on developing synergistic combinations of conventional genotoxic chemo­therapeutic agents with diverse HR inhibitors [3c, 3d] as a means to expand the well-tolerated therapeutic window for such therapies, and to forestall the development of chemoresistance.  
   3a.   Finn GK, Kurz BW, Cheng RZ, Shmookler Reis RJ  (1989)  Homologous plasmid recombination is elevated
   in immortally transformed cells.  Mol. Cell. Biol. 9: 4009-4017. PMCID: PMC362463
   3b. Shammas MA, Shmookler Reis RJ, Koley H, Batchu RB, Li C, Munshi N.  (2008)  Dysfunctional homologous
   recombination mediates genomic instability and progression in myeloma.  Blood 113: 2290-2297. 
   PMID:19050310  PMCID: PMC2652372
  ​ 3c. Alagpulinsa DA, Yaccoby S, Ayyadevara S, Shmookler Reis RJ (2015). A peptide nucleic acid targeting
   nuclear RAD51 sensitizes multiple myeloma cells to melphalan treatment.  Cancer Biol Therapy 16: 976–986. 
   PMID: 25996477, PMCID: PMC4622566
  ​ 3d. Alagpulinsa DA, Ayyadevara S, Yaccoby S, Shmookler Reis RJ. (2016) A cyclin-dependent kinase inhibitor,
   dinaciclib, impairs homologous recombination and sensitizes multiple myeloma cells to PARP inhibition. Mol
   Cancer Ther  15: 241–250.  PMID: 26719576, PMCID: PMC4747838

4. Genetic, reverse-genetic and theoretical analyses of aging and age-progressive diseases.  We mapped loci that influence bone density in mice, and that contribute to post-maturity loss of bone, and tested the functional roles of candidate genes [4a]. We created a genetic knockout for the Pirin gene implicated in our mouse and human studies [1d], and found that it recapitulates several osteopenia-associated traits, but only in females. Aspirin exerts anti-inflammatory effects in C. elegans, where it extends life­span and delays physiological and molecular indices of aging; by use of RNA interference (RNAi) knockdown, we showed that benefits are mediated through both Jun and insulinlike signaling pathways [4b] to reduce aggregates. In gene network models, stability theory predicts that gene expression will deviate increasingly as organisms age, becoming stress-sensitive and ultimately unstable in most species [4c]. Negligibly senescent species, how­ever, remain stress resistant and stable. Gompertz’ law and plateauing of age-dependent rise in mortality are features that arise naturally in this model. Gene networks also helped to define broadly conserved pathways for dietary restriction and life-extension [4d].
   4a. Szumska D, Beneš H, Kang P, Weinstein RS, Jilka RL, Manolagas S, Shmookler Reis RJ.  (2007) A novel locus
   on the X chromosome regulates post-maturity bone density changes in mice. Bone 40:758-766.
   4b. Ayyadevara S, Dandapat A, Bharill P, Hu CP, Khaidakov M, Mitra S, Shmookler Reis RJ, Mehta JL (2013)
   Aspirin inhibits oxidant stress, reduces aging-associated functional decline and pro­longs life­span of
   Caenorhabditis elegans. Antioxid Redox Signaling 18:481-490. PMID: 22866967
   4c. Kogan V, Molodtsov I, Menshikov LI, Shmookler Reis RJ, Fedichev P (2015) Stability analysis of a model
   gene network links aging, stress resistance, and negligible senescence. Science Rep 5: 13589. doi:
   10.1038/srep13589. PMID:26316217, PMC4551969  Ranked in 100 most-read (Sci Rep 2015)
   4d. Wuttke D, Connor R, Vora C, Craig T, Li Y, Wood S, Vasieva O, Shmookler Reis RJ, Tang F, de Magalhães JP
   (2012) Dissecting the gene network of dietary restriction to identify evolutionarily conserved pathways and
   new functional genes. PLoS Genet 8: e1002834. PMC3415404

5. Advances in gene-mapping methodology and in “omic data” meta-analyses.  We developed one of the first two gene-mapping protocols in aging and longevity research [5a; see also Lai & Mackay, 1993], and the first such protocol for C. elegans, used to characterize and identify for the first time in a metazoan, loci with strong effects on lifespan and their interactions [5a]. We invented a novel, highly-multiplexed method to genotype simultaneously many dimorphic markers, thus greatly accelerating the process of genetic fine-mapping [5b]. Both this method, and a parallel method for differential transcript display, were based on our previous determination of conditions under which 3’ mismatch absolutely blocks DNA chain extension [Thweatt et al. 1990].  We developed a novel approach to GO/pathway analysis (of transcript expression; also applied to proteomic and metabolomic data), to combine the p values for differential expression of all genes in each GO/pathway category, thus greatly improving the sensitivity and power of such meta-analyses [5c]. We also developed a novel protocol to normalize data by array or by group, in order to detect and compensate for systematic biases between groups [5d].
   5a. Ebert RH II, Cherkasova VA, Dennis RA, Wu JH, Ruggles S, Eudy Perrin T, and Shmookler Reis RJ (1993). 
   Longevity-determining genes in Caenorhabditis elegans: Chromosomal mapping of multiple noninteractive
   loci.  Genetics 135: 1003–1010.  PMCID: PMC1205733
   ​5b. Ayyadevara S, Thaden JJ, Shmookler Reis RJ. (2000)  Anchor Polymerase Chain Reaction Display: A high
   throughput method to resolve, score and isolate dimorphic genetic markers based on interspersed repetitive
   DNA elements. Anal. Biochem. 284:19–28.
   ​5c. Shmookler Reis RJ, Ayyadevara S, Crow WA, Lee TW, Delongchamp R. (2012) Gene categories differentially
   expressed in C. elegans age-1 mutants of extraordinary longevity: New insights from novel data-mining
   procedures.  J Gerontol Biol Sci 102: 672–681.
   5d​. Lee TW, Delongchamp RR, Kim W, Shmookler Reis RJ.  (2016) Use of p-value plots to diagnose and remedy
   problems with statistical analysis of microarray data. Genes Genomics 38: 45–52.

Complete List of Published Work in My Bibliography (peer-reviewed journal publications):
     

D.  Research Support

Ongoing Support

1.  Analysis and Therapy of Age-Dependent Proteostasis Failure in Neurodegeneration (GRANT12246991)
      Agency: VA                                          Period of support:  4/1/2013 – 3/31/2017
      Role:  Principal Investigator             No percent effort specified
      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.

2.   Senior Research Career Scientist Award      
      Agency: VA                                           Period of support:  10/01/2012 – 09/30/2019
      Role:  Awardee                                    No percent effort specified
The RCSA is a competitive, merit-based award to support continuity of basic research by successful VA career scientists.  Previous RCS awards: 10/01/2002 – 9/30/2007; 10/01/2007 – 9/30/2012.    

3.   Early Events in Alzheimer Pathogenesis.  P01 AG012411-17A1 (WST Griffin, PI),
      Agency:  NIH/NIA                                Period of support: 09/2016 – 06/2021
      Role: Project 3 Leader                        50% effort (6 cal. months)
Project 3 addresses the roles of protein aggregation in Alzheimer’s and other neurodegenerative diseases, and testing of small drug libraries developed by Dr. Peter Crooks (Core D) for protection from aggregation.

Completed Research Support (last 10 years):
1.         Mechanisms and Therapies for Extreme Longevity
      Agency: Life Extension Foundation    Period of support:  05/01/13–10/31/16 (renewable indefinitely)
            Role:  Principal Investigator                No percent effort specified
The aims of this proposal are to (1.) identify and quantify PIP3-binding proteins from wild-type and PI3K-null worms; (2.) identify and characterize proteins in transcription complexes that distinguish ultra-long-lived worms from normal worms; (3.) test PIP2 analogs, and other drugs computer-designed to inhibit PI3KCS-I, to assess their affinity and specificity, and effects on survival traits of worms and human cultured cells.

2. Arkansas Claude Pepper OAI Center at UAMS (J. Wei P.I.); Pilot and Exploratory Studies Core
      Agency: NIA/NIH                                Period of support:  9/1/2011 – 8/31/2016.        
      Role: Core Leader                              Percent effort: 25% of UAMS effort
     This grant provides infrastructure and research support for studies of age-dependent metabolic pathway activities in humans and animal models, using stable-isotope technologies.

3.   Range of variation in the duration of C. elegans dauer and post-dauer survival
      Agency:  SENS Foundation              Period of support: 04/01/2012 – 03/31/2016 (renewable)
      Role: Principal Investigator               No percent effort specified
     
4.   Homologous recombination in multiple myeloma development & progression. Robert J. Shmookler Reis,PI. Agency: VA Merit Review                             Period of support: 04/01/2009 – 03/31/2013. 
     Role: Principal Investigator

5.   NIH R01, Role of glutathione transferases in life span extension of C. elegans.  Piotr Zimniak, PI
      Agency: NIH/NIA.                                          Period of support: 12/01/2006 – 11/30/2011. 
      Role: Co-investigator

6.  NIH P01   AG13918 (S. Manolagas, P.I.)
      Agency: NIH/NIA                                           Period of support: 12/01/2001 – 11/30/2011. 
      Role: Project Leader, Project 3: Genetics of Osteopenia
                       
7.  NIH P01 AG20641: “Metabolic Mechanisms Limiting and Protecting Longevity”. 
     Agency:  NIH/NIA.                                         Period of support:  02/15/03 – 01/31/08.
     Role: Principal Investigator, Project Leader, Core Leader