I aim to identify the synapse centered microRNAs so called synaptosomal miRNA (Syn-miRs) and their roles in neurodegenerative diseases specially in Alzheimer’s. Active synapses are the key components for synaptic health and normal & healthy brain functioning. Molecular and cellular components of synase are very crucial for neurotransmission and to maintain healthy synaptic and cognitive functions. Synaptic loss and dysfunctions are the main pathological hallmarks of Alzheimer’s disease.
MiRNAs enriched at synapse, directly regulate the local protein synthesis involved in multiple synaptic functions and governing synaptic plasticity. However, the role of synaptosome-specific miRNAs is not determined in the progression of AD and other neurodegenerative diseases. My lab studying the impact of synaptosomal miRNAs on neuron function and several synapse events- synaptic activity, axonal transport, synapse mitochondrial function, synaptic vesicle trafficking, release and cycling, altered Ca++ influx, neurotransmitter release, impaired receptors, inflammation and synaptotoxicity. We are utilizing multidisciplinary approaches of cell and molecular biology techniques, protein biochemistry, omics-based approaches, patch-clamp analysis, live-cell imaging, mutant and transgenic mouse models, and mouse cognitive behavior.
I did my Ph.D. from Post Graduate Institute of Medical Education and Research, Chandigarh, India. There, I worked in molecular genetics lab and my research project was focused on microRNA (miRNA) expression analysis in Hepatitis C patients and in-vitro cell culture system. MiRNAs are the class of small non-coding RNA molecules, regulates gene expression by binding with the 3’-UTR of their specific target mRNAs and implicated in various human diseases including cancer, cardiovascular diseases, liver diseases, viral infection, and diabetes and in neurodegenerative disorders. MiRNAs mainly functions in the modulation of gene expression, extracellular secretion for cellular communication. During disease state miRNA are deregulated in the cells and could be used as a peripheral biomarker in various human diseases. My interest was to explore the biomarker and therapeutic potential of miRNAs in different human disease. I studied the role of miRNA-122 (miR-122) in hepatitis C virus replication and tumor suppression. First, I studied the expression of miR-122 in HCV (genotype-3) patients. MiR-122 expression was found to be upregulated in HCV patients’ serum samples compared to healthy controls. High expression level of miR-122 was correlated with the clinical parameters (viral load and liver function test) of patients. Besides, I found that miR-122 promotes the HCV replications in different hepatic cells lines (Huh-7 and HepG2) and useful for in-vitro propagation of HCV to study the chemotherapeutic agents. On the otherhand I studied the anti-tumor properties of miR-122. Our in-vitro study showed that miR-122 induced the apoptotic cell death by suppressing the expression of several anti-apoptotic genes, hence it could be an anti-tumor molecule. I joined Garrison Institute on Aging TTUHSC, Lubbock, Texas, as a postdoc fellow in 2015. My research project was focus on the peripheral circulatory miRNAs in Alzheimer disease (AD) and their therapeutic potential. Briefly, we screened serum samples collected from AD patients’, MCI individuals and healthy controls for the miRNA expression analysis using Affymetrix microarray. We identify, miR-455-3p as one of the potential miRNAs found to be upregulated in AD cases relative to MCI and healthy controls. We validated our findings on different AD sources- brain, CSF, fibroblasts, B-lymphocytes, cell lines and AD mouse models. We also find the role of miR-455-3p in regulation of APP protein processing and mitochondrial biogenesis. Our aim was to identify the potential miRNA candidate as a novel biomarker for AD which might aid in improving the early diagnosis, prognosis of AD and developing effective chemotherapeutic agents and ameliorate the clinical outcome. In last year, February 2019, our lab moved to Internal Medicine Department at TTUHSC. Here, also I am continuing the same work- developing miR-455-3p transgenic and knockout mouse models to study the biomarker and therapeutic potential of miR-455-3p in AD.
During my postdoc I learned the mouse work such as breeding, weaning, genotyping, and dissection of mouse brain. I am regularly monitoring and maintaining the colonies of transgenic and knockout mice such as APP transgenic, APP knockout, Tau transgenic, Tau knockout, VDAC transgenic, MiR-455-3p Transgenic, MiR-455-3p Knockout, TallyHO, Drp1 transgenic and BACHD mice. I got expertise in mouse behavior testing. Dr. Reddy lab having a well-equipped setup for mice cognitive behavior testing such as- Morris water maze, Y maze, Open-field, Rotarod, Fear conditioning and Tail suspension tests etc. I also learned the therapeutic intervention of chemically synthesized molecules (SS31, Mdivi1 and DDQ) in AD mouse models.
Recently, I joined an Assistant Professor in the Department of Molecular and Translational Medicine at TTUHSC El Paso in El Paso, Texas. My lab focus is to study the roles of synapse microRNAs in the Alzheimer’s disease.
- K99AG065645 grant Kumar S. (PI) 09/15/2020 - 06/30/2022
“Synaptosomal MicroRNAs, Synaptic Damage and Cognitive Decline in Alzheimer's Disease”. The overall objective of this grant application is to understand the role of synaptosomal miRNAs in the Alzheimer’s disease pathogenesis. Total Award amount: $190,130.
- R00AG065645 grant Kumar S. (PI) 09/1/2022 - 06/30/2025
“Synaptosomal MicroRNAs, Synaptic Damage and Cognitive Decline in Alzheimer's Disease”. The overall objective of this grant application is to understand the role of synaptosomal miRNAs in the Alzheimer’s disease pathogenesis. Total Award amount: $741,750.
- Positions and Honors
2022-Present: Assistant Professor, Molecular and Translational Medicine, TTUHSC El Paso, El Paso, Texas, USA
2021-2022: Research Assistant Professor, Internal Medicine Department, TTUHSC, Lubbock, Texas, USA
2019-2021: Postdoctoral Fellow, Internal Medicine Department, TTUHSC, Lubbock, Texas, USA
2015-2019: Postdoctoral Fellow, Garrison Institute on Aging, TTUHSC, Lubbock, Texas, USA
2014-2015: Survey Manager Parasitology, PGIMER, Chandigarh, India
2009-2014: Senior Research Fellow, Indian Council of Medical Research, PGIMER, Chandigarh, India
2007-2008: Junior Research Fellow, Indian Council of Medical Research, PGIMER, Chandigarh, India
2005-2007: Tutor in Biotechnology at IIMT college of Medical Science, Meerut, India
2004-2004: Undergraduate researcher at CDRI, Lucknow, India
Other Honors and awards
2022--Received second best oral presentation award in 14th Annual Research Symposium - April 19-21, at TTUHSC El Paso.
2020--Received NIA NIH Pathway to Independence Career Development Award (K99/R00) for 5 years.
2018--Best poster award at Regional Healthy Aging and Dementia Research Symposium at Garrison Institute on Aging of Texas Tech University Health Sciences Center, Lubbock, Texas, USA.
2015-- Council of Scientific and Industrial Research (CSIR)-Postdoc Research Associate fellowship from CSIR-New Delhi, India
2013--International Travel Award Indian Council of Medical Research (ICMR), New Delhi, India
2012--Travel award from Indian National Association for the Study of Liver PGIMER, Chandigarh, India
2008-2014 -- Junior/Senior Research Fellowship-Indian Council of Medical Research, New Delhi, India
2007-- Graduate Aptitude Test in Engineering fellowship by Indian Institute of Technology (IIT) Kanpur, India
Grant Review and Research Judge
2021--Research Poster Competition Judge Annual Student Research Week TTUHSC, Lubbock, Texas, USA.
2020--Research Poster Competition Judge Annual Student Research Week TTUHSC, Lubbock, Texas, USA.
2019--Research Poster Competition Judge Annual Student Research Week TTUHSC, Lubbock, Texas, USA.
2018--Research Poster Competition Judge Annual Student Research Week TTUHSC, Lubbock, Texas, USA.
2018-- Brigid Ryan for the position of AMRF Postdoctoral Fellowship, The University of Auckland, Auckland, New Zealand.
Reviewer for Scientific Journals
PLOS ONE, Frontiers in Aging Neuroscience, Journal of Clinical Interventions in Aging (Dove press), Bioscience Reports (Portland press), Cell Communication & Signaling (Springer nature), Molecular Medicine Reports (Spandidos publications), Experimental and Therapeutic Medicine (Spandidos publications), Oncology Letters (Spandidos publications), ACS Chemical Neuroscience (ACS publications), Journal of Alzheimer’s Disease, Chemico-Biological Interactions, Acta Haematologica (Kargar press), Brain Research (Elsevier), The FASEB journal, American Journal of Translational Research, BMC Neuroscience,
Membership of Research Societies
2017-2022-- Society for Neuroscience (SFN) (Faculty Member)
2022- Alzheimer’s Association International Conference (AAIC) (Faculty Member)
2010-- Association of Basic Medical Scientist (ABMS) (Life Member)
2022-- US patent on “Synaptosomal miRNAs and Synapse Functions in Alzheimer's Disease” TTU Ref. No. 2022-016, U.S. Provisional Pat. App. No. 63/332,866 on April 20, 2022.
2020-- US-2020-0255900-A1 (Aug 13, 2020) “MicroRNA-455-3p as a Peripheral Biomarker for Alzheimer's Disease”
C. Contributions to Science
Early and Graduate Career: In my early research career, as a summer intern my undergraduate research was focused on the Leishmania donovani. My research project was to search the unique soluble antigen against Leishmania donovani species. My project title was “Effect of soluble leishmania donovani antigen against the peritoneal macrophage of hamster”. I worked on hamster, where I treated hamster macrophages with Leishmania strains and studied the antigen generation using cellular and molecular biology techniques.
My graduate research study was to investigate the “Role of liver-specific microRNA-122 (miR-122) in hepatitis C virus (HCV) replication and tumor suppression”. In the first part of study, status of circulating miR-122 was evaluated in the serum samples of chronic hepatitis C (CHC) patients infected with HCV genotype-3. MiR-122 expression was found to be significantly upregulated in the patients relative to healthy controls. Interestingly, elevated level of miR-122 was significantly correlated with patients HCV viral load, ALT and AST activity, suggesting its possible role as a diagnostic molecule (Kumar et al. Disease Markers, 435476: 2014). Next, I studied the role of miR-122 was investigated in HCV genotype-3 replication. The hepatic and non-hepatic cell lines (Huh-7, HepG2 & HeLa) were co-transfected with miR-122 expression vector and HCV plasmid (pBRTM/HCV) and co-infected with miR-122 expression vector and HCV (genotype-3) patients’ serum. Expression of HCV NS-5b gene was monitored in these cells to confirm the HCV replication in presence of miR-122. Immunofluorescence assay, flow cytometry and real-time PCR analysis depicted that HCV replication was significantly enhanced by miR-122 at different time intervals (Kumar et al. Journal of Clinical and Experimental Hepatology, 2011). In third part of study anti-tumor properties of miR-122 was explored in-vitro. Since miR-122 target some proto-oncogene (cyclinG1 & bcl-w) and modulates their activity. Cells were induced with miR-122 expression vector and cell proliferation and cell death assays were performed. MiR-122 positive cells showed a consistent increased of apoptotic cells at different time intervals. Interestingly, expression of miR-122 target genes cyclinG1 & bcl-w and foxM1b (act as proto-oncogenes during carcinomas) were significantly reduced by miR-122 (Kumar et al. Experimental Biology and Medicine 242, 436-440: 2017). These observations suggested a possible anti-oncogenic role of miR-122 in cancer.
- Kumar S, Batra A, Kanthaje S, Ghosh S, Chakraborti A. Crosstalk between microRNA-122 and FOX family genes in HepG2 cells. Exp Biol Med (Maywood). 2017 Feb; 242(4):436-440.
- Kumar S, Chawla YK, Ghosh S, Chakraborti A. Severity of hepatitis C virus (genotype-3) infection positively correlates with circulating microRNA-122 in patients’ sera. Dis Markers. 2014; 2014: 435476.
- Kumar S, Chawla, YK, Ghosh S, Chakraborti, A. Over-expression of microRNA-122 (miR-122) induces apoptosis by targeting cyclinG1 and Bcl-w genes in-vitro. Journal of Clinical and Experimental Hepatology 2012. 2, Number 1 (Suppl).
- Kumar S, Chawla YK, Ghosh S, Chakraborti A. Inducible Expression of MicroRNA-122 (miR-122) in Hepatic and Non-hepatic Cells. Journal of Clinical and Experimental Hepatology 2011.1, Number 1 (Suppl).
Postdoctoral Career: Dr Reddy lab is working on several aspects of Alzheimer’s disease (AD) such as miRNAs, mitochondrial dynamics, and interactions of APP, Drp1, Tau and voltage-dependent anion channel protein1 (VDAC1) proteins in Alzheimer’s disease. As a postdoctoral fellow, my research projects are mainly focused on the role of miRNAs in Alzheimer’s disease, Aging and stroke.
(1) Alzheimer’s disease and miRNAs- The major focus of my study was to identify the potential peripheral circulatory miRNAs as biomarker for AD. In disease state the miRNAs levels are deregulated in the cells and/or infected tissue. Deregulation of miRNAs levels influence in the various body fluids such as serum, plasma, urine, saliva, milk, cerebrospinal fluid. Quantification of miRNAs levels in peripheral circulation provides the important information about the disease outcomes (Kumar et al. Biochim Biophys Acta 1862,1617-1627: 2016). We hypothesized that in AD patients, circulating miRNAs levels changed in AD state relative to healthy state. To achieve our aim, we screened the serum samples obtained from Alzheimer patients’ Mild cognitive impairment (MCI) individuals and healthy controls subjects for the miRNA expression analysis using Global Affymetrix miRNA microarray. We used high throughput techniques to isolate miRNAs from serum and quantification of their expression. The disease specific deregulated miRNAs and some unique miRNAs was identified by microarray data analysis. Significantly deregulated miRNAs were selected and further validated on large number of AD serum samples, AD postmortem brains, AD mouse model, AD cell lines by qRT-PCR analysis. Our careful validation analysis on different AD sources identified microRNA-455-3p as potential biomarker for AD (Kumar et al. Human Molecular Genetics 26, 3808-3822: 2017). Further, we validated the expression of miR-455-3p in Fibroblasts, B-lymphocytes obtained from AD patients and AD postmortem brains tissues obtained from NIH NeuroBioBank. All validation study concluded the upregulation of miR-455-3p in AD cases relative to healthy controls (Kumar et al. Frontiers in Aging Neuroscience 10, 41: 2018). Next, we planned to study the roles and complete molecular functions of miR-455-3p in AD. Why it is upregulated in AD and is it a good or bad molecule in AD. Our in-vitro study showed the protective role of miR-455-3p against mutant APP cDNA induced amyloid-β toxicities in neurons. MiR-455-3p was found protective against- 1) abnormal APP processing, 2) mitochondrial biogenesis, 3) mitochondrial dynamics 3) synaptic activity and 5) cell survival and cell proliferation. (Kumar et al. Biochim Biophys Acta Mol Basis Dis, 2019 Sep 1;1865(9):2428-2440.). Recently, we summarized our miR-455-3p research journey in a review and discuss the role of miR-455-3p in other human diseases (Kumar and Reddy. J Alzheimers Dis. 2019;72(s1):S117-S130). Currently, we are working on the APP transgenic and APP knockout mice to determine the age-dependent expression of miR-455-3p and its status in different tissues during disease progression. We also studying the brain specific localization of miR-455-3p in APP transgenic and APP knockout mice.
- Kumar S, Morton H, Sawant N, Orlov E, Bunquin LE, Pradeepkiran JA, Alvir R, Reddy PH. MicroRNA-455-3p improves synaptic, cognitive functions and extends lifespan: Relevance to Alzheimer's disease. Redox Biol. 2021 Nov 9;48:102182.
- Kumar S, Reddy AP, Yin X, Reddy PH. Novel MicroRNA-455-3p and its protective effects against abnormal APP processing and amyloid beta toxicity in Alzheimer's disease. Biochim Biophys Acta Mol Basis Dis. 2019 Jun 8. pii:S0925-4439(19)30199-1.
- Kumar S, Reddy PH. MicroRNA-455-3p as a Potential Biomarker for Alzheimer's disease: An Update. Front Aging Neurosci. 2018 Feb 23;10:41.
- Kumar S, Vijayan M, Reddy PH. MicroRNA-455-3p as a potential peripheral biomarker for Alzheimer's disease. Hum Mol Genet. 2017 Oct 1;26(19):3808-3822.
(2) Aging and miRNAs- Dr Reddy lab also studying the role of miRNAs in the aging process. Role of miRNA has been investigated in aging process and age-related human diseases (Kumar et al. Progress in Molecular Biology and Translational Science, Molecular Biology of Aging 146, 47–94: 2017). Expression levels of miRNAs are changed in the cell in response to various cellular and molecular changes such as cellular senescence, oxidative stress, telomere shortening, DNA damage, protein mis-folding, nutrient sensing and epigenetics (William et al. Ageing Research Review 35, 350-363: 2017). Our main focus is to identify the potential miRNA biomarker for healthy aging process and study the age dependent miRNA expression changes in healthy (wild type) and AD (APP) mouse model.
- Gowda P, Reddy PH, Kumar S. Deregulated mitochondrial microRNAs in Alzheimer's disease: Focus on synapse and mitochondria. Ageing Res Rev. 2022 Jan;73:101529.
- Kumar S, Vijayan M, Bhatti JS, Reddy PH. MicroRNAs as Peripheral Biomarkers in Aging and Age-Related Diseases. Progress in Molecular Biology and Translational Science, Molecular Biology of Aging 146, 2017, Pages 47–94.
- Williams J, Smith F, Kumar S, Vijayan M, Reddy PH. Are microRNAs true sensors of ageing and cellular senescence? Ageing Res Rev. 2017 May;35:350-363.
- Bhatti JS, Kumar S, Vijayan M, Bhatti GK, Reddy PH. Therapeutic Strategies for Mitochondrial Dysfunction and Oxidative Stress in Age-Related Metabolic Disorders Progress in Molecular Biology and Translational Science, Molecular Biology of Aging 146, 2017, Pages 13-46.
(3) Stroke and miRNAs- Dr Reddy lab also investigated the role miRNA in stroke, a very common neurological disease. MiRNA-mediated post-transcriptional regulation is poorly understood in vascular biology and pathology (Vijayan et al. Progress in Molecular Biology and Translational Science, Molecular Biology of Aging 146, 95-126: 2017). We analyzed the miRNAs expression levels in IS serum samples and healthy controls using Illumina deep sequencing analysis and identified differentially expressed miRNAs. Differentially expressed miRNAs were further validated using qRT-PCR assay in postmortem IS brains, lymphoblastoid IS cell lines, oxygen and glucose deprivation/ reoxygenation-treated human and mouse neuroblastoma cells, and mouse models of hypoxia and ischemia (HI)-induced stroke. Interestingly, we found several novel and previously unreported miRNAs in IS patients relative to healthy controls.
- Vijayan M, Kumar S, Yin X, Zafer D, Chanana V, Cengiz P, Reddy PH. Identification of novel circulatory microRNA signatures linked to patients with ischemic stroke. Hum Mol Genet. 2018 Jul 1;27(13):2318-2329.
- Vijayan M, Kumar S, Bhatti JS, Reddy PH. Molecular Links and Biomarkers of Stroke, Vascular Dementia, and Alzheimer’s Disease. Progress in Molecular Biology and Translational Science, Molecular Biology of Aging 146, 2017, Pages 95-126.
(4) Cell Culture/Animal Studies and Alzheimer’s disease - I am working on other projects, including cell culture and animal studies running in Dr Reddy lab, identifying water soluble molecular inhibitors that can reduce the levels of Aβ, and tau levels and also inhibit abnormal interactions between, Aβ and phosphorylated tau and Aβ with other proteins. We also studying the protective effect of soluble molecular inhibitors on APP and Tau transgenic mice at molecular level and by performing mice cognitive behavior tests.
- Hegde V, Vijayan M, Kumar S, Akheruzzaman M, Sawant N, Dhurandhar NV, Reddy PH. Adenovirus 36 improves glycemic control and markers of Alzheimer's disease pathogenesis. Biochim Biophys Acta Mol Basis Dis. 2019 Nov 1;1865(11):165531.
- Reddy PH, Yin X, Manczak M, Kumar S, Pradeepkiran JA, Vijayan M, Reddy AP. Mutant APP and amyloid beta-induced defective autophagy, mitophagy, mitochondrial structural and functional changes and synaptic damage in hippocampal neurons from Alzheimer's disease. Hum Mol Genet. 2018 Jul 15;27(14):2502-2516.
- Reddy PH, Manczak M, Yin X, Grady MC, Mitchell A, Tonk S, Kuruva CS, Bhatti JS, Kandimalla R, Vijayan M, Kumar S, Wang R, Pradeepkiran JA, Ogunmokun G, Thamarai K, Quesada K, Boles A, Reddy AP. Protective Effects of Indian Spice Curcumin Against Amyloid-β in Alzheimer's Disease. J Alzheimers Dis. 2018;61(3):843-866.
Complete List of Published Work in my Bibliography: