Catalyzing Degradation of Tau Aggregates

  • Research Info
  • Team Members
  • Publications
  • Photos
  • Funding
  • Research Info
  • Team Members
  • Publications
  • Photos
  • Funding

Tau is the major microtubule-associated protein (MAP) in mature neurons in the central nervous system. The MAPT (microtubule-associated protein tau) gene encodes for six splice variants that are highly soluble; their main function is interacting and stabilizing microtubules, along with other MAPs. The ability of tau to stabilize the microtubule is aided by its phosphorylation.

Hyperphosphorylation of tau depresses its biological activity and can lead to destabilization of microtubules. Also, hyperphosphorylation of tau proteins can cause it to aggregate into oligomers, which in turn assemble into helical and straight insoluble filaments and ultimately mature into neurofibrillary tangles (NFTs).

In Alzheimer’s disease brain, tau is three to four-fold more hyperphosphorylated than in the normal adult brain, leading to a pathological buildup of NFTs. The accumulation of NFTs comprising hyperphosphorylated tau is also observed in normal aging (PMID: 24548606).

Various other neurodegenerative diseases, collectively called tauopathies – including Pick’s disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal lobar dementia with Parkinsonism linked to chromosome 17 (FTDP-17), and dementia pugilistica – are also caused by tau aggregation.

In consultation with SRF-supported biotech company Covalent Bioscience, SENS Research Foundation has initiated a project to develop a novel way to remove abnormally aggregated tau as a therapeutic intervention with potential relevance to mitigating normal age-dependent cognitive decline, as well as for tauopathies like Alzheimer’s disease and related dementias.

Covalent Bioscience have previously demonstrated the therapeutic potential of catabodies in a recent publication targeting Transthyretin (TTR) that forms misfolded b-sheet aggregates responsible for age-associated amyloidosis. In this paper they have described catabodies from healthy humans without amyloidosis that degraded misfolded TTR (misTTR) without reactivity to the physiological tetrameric TTR (phyTTR) (PMID: 24648510).

Team Members

We’re Hiring!

Please visit the Work With Us page to learn about available positions.

Principal Investigator

Dr. Amit Sharma

Dr. Amit Sharma

Dr. Amit Sharma was awarded a Master’s degree in Biomedical Sciences from Delhi University, India.  He received his PhD in 2009 in Biotechnology from University of Pune for his work demonstrating microRNA regulation of cytokines involved in allergic inflammation in mice model. Dr. Sharma’s postdoctoral research at the Buck Institute, Novato California involved investigating novel molecular regulatory pathways involved in genotoxic stress and cellular senescence in invertebrate and mammalian models.

Dr. Sharma has recently joined SENS Research Foundation as Group Lead in the Senescence Immunology Research Group. His research focus involves studying how aging and senescence affects the immune system and his research group will also investigate strategies to harness the immune system in mitigating deleterious effects of senescent cells with translational focus.

Publications

Previous Publications by Dr. Sharma

Sharma A, Kumar M, Aich J, Hariharan M, Brahmachari S.K, Agrawal A and Ghosh B. Post-Transcriptional Regulation of Interleukin-10 Expression by hsa-miR-106a. Proc Natl Acad Sci U S A. 2009; 106: 5761-6. PMC 2659714

Sharma A, Kumar M, Ahmad T, Mabalirajan U, Aich J, Agrawal A and Ghosh B. Antagonism of mmu- mir-106a attenuates asthma features in allergic murine model. JAP, 2012.

Kumar M, Ahmad T, Sharma A, Mabalirajan U, Kulshreshtha A, Agrawal A, Ghosh B. Let-7 microRNA- mediated regulation of IL-13 and allergic airway inflammation. J Allergy Clin Immunol. 2011. PMID 21616524 

Kumar S, Sharma A and Madan B, Singhal V and Ghosh B. Isoliquiritigenin inhibits IkappaB kinase activity 
and ROS generation to block TNF-alpha induced expression of cell adhesion molecules on human 
endothelial cells. Biochem Pharmacol. 2007; 73:1602-12. 


Tanveer A, Mabalirajan U, Sharma A, Ghosh B, Agrawal A. Simvastatin Improves Epithelial Dysfunction 
and Airway Hyperresponsiveness: From ADMA to Asthma. Am J Respir Cell Mol Biol. 2011 Apr;44 (4):531- 
9. PMID 2055877

Ghosh B, Kumar S, Balwani S, Sharma A. Cell adhesion molecules: therapeutic targets for developing 
novel anti-inflammatory drugs. Advanced Biotech. 2005; 4:13-20. 


Sharma S, Sharma A, Kumar S, Sharma S.K. and Ghosh B. Association of TNF haplotypes with Asthma, 
Serum IgE levels and correlation with serum TNF-α levels. Am J Respir Cell Mol Biol. 2006; 35: 488-95.

Sharma A, Joseph Wu. MicroRNA Expression Profiling of Human Induced Pluripotent and Embryonic Stem Cells. Methods in molecular biology, a part in Springer Science. PMC 3638037

Sharma A, Diecke S, Zhang WY, Lan F, He C, Mordwinkin NM, Chua KF, Wu JC. The role of SIRT6 protein in aging and reprogramming of human induced pluripotent stem cells. J Biol Chem. 2013. PMID 23653361.

Lang S, Bose N, Wilson K, Brackman D, Hilsabeck T, Watson M, Beck J, Sharma A, Chen L, Killlilea D, Ho S, Kahn A, Giacomini K, Stoller M, Chi T, Kapahi P. A conserved role of the insulin-like signaling pathway in uric acid pathologies revealed in Drosophila melanogaster. bioRxiv 387779

Akagi K, Wilson K, Katewa SD, Ortega M, Simmons J, Kapuria S, Sharma A, Jasper H, Kapahi P. Dietary restriction improves intestinal cellular fitness to enhance gut barrier function and lifespan in D. melanogaster. PloS Genet. 2018 Nov 1; 14(11):e1007777. PMC6233930.

Sharma A, Akagi K, Pattavina B, Wilson KA, Nelson C, Watson M, Maksoud E, Ortega M, Brem R, Kapahi P. Musashi expression in intestinal stem cells attenuates radiation-induced decline in intestinal homeostasis and survival in Drosophila. Sci Reports. 2020 Nov 5;10(1):19080.

Full list of published work as found in My Bibliography:

https://www.ncbi.nlm.nih.gov/sites/myncbi/amit.sharma.2/bibliography/55316754/public/?sort=date&direction=ascending

Photos

Resources

Funding

To support our work please consider making a donation to SENS Research Foundation!

Thanks to our existing funders:

Engineering New Mitochondrial Genes to Restore Mitochondrial Function (MitoSENS)

  • Research Info
  • Team Members
  • Publications
  • Photos
  • Funding
  • Research Info
  • Team Members
  • Publications
  • Photos
  • Funding

Mitochondria perform and support several vital functions in a cell, and the alternate genome, mtDNA, plays a critical role in organelle maintenance. There is increasing evidence that mitochondrial function declines with age, and that dysfunctional mitochondria adversely contribute to several metabolic and neuromuscular diseases. Our goal is to address age-acquired and inborn errors of mutation in the mtDNA using a gene therapy approach. We are exploring:

  1. allotopic expression (expressing mtDNA genes from the nucleus), and
  2. whole-organelle replacement

as strategies to revitalize mitochondrial function. Our multidisciplinary approach employs cell culture and mouse models to achieve our objectives.

Allotopic Expression of Proteins Encoded in the Mitochondrial DNA

Mitochondria are the ‘power plants’ in every mammalian cell responsible for the efficient conversion of nutrients to energy. Impaired mitochondrial function and mutations in mtDNA contribute to several age-related illnesses, including Alzheimer’s Disease, Parkinson’s disease, and sarcopenia. Point mutations in any of the 13 protein-coding regions, as well as micro- and macro- deletions in the mtDNA, lead to several monogenic and organelle-specific diseases (MELAS, MEERF, LHON, Leigh’s disease to name a few). However, alterations in the OriH / OriL regions in the mtDNA can lead to global impairment in the transcription and translation of the mitochondrial genome. The mitochondrial proteome, however, consists of ~1400 proteins of which all except for the 13 polypeptides translated on the mitochondrial genome originate from the host’ nucleus. Over the course of evolution, mitochondria have developed sophisticated mechanisms to import these nuclear mitochondrial proteins. These mechanisms employ intricate translocases and signals, which are directed to different regions within the organelle.

The goal of this project is to determine how we might achieve optimal parameters for coding and non-coding regions to efficiently express and target the 13 mtDNA genes to the respiratory chain from the nucleus. Toward this end, we employ molecular biology, biochemistry and computational strategies, and refine and build on our existing knowledge of import conditions for the numerous nuclear mitochondrial proteins already delineated. We use patient-derived cybrids and animal models in assessing the functional utility of our constructs. Ultimately, we aim to express the mtDNA genes individually or in combination to overcome age-related changes to the mtDNA and improve overall organelle fitness. Please see here for recent progress on this project.

Reversing Age-Induced Mitochondrial Damage through Organelle Transplantation

Intercellular mitochondria exchange occurs naturally in the human body between cell types, typically between healthy and damaged cells. Three different transfer mechanisms have been observed:

  1. stem cells release naked mitochondria that are taken up by other cells,
  2. mitochondria are released extracellularly, enclosed in vesicles that are in turn taken up by recipient cells (possibly via endocytosis), or
  3. mitochondria migrate from one cell to another through specialized structures in vivo, such as nanotubes.

The goal of this project is to evaluate the potential of mitochondrial transfer to counteract age-related loss of tissue function. We aim to develop strategies to purify viable mitochondria and deliver them to target regions in the body.

Team Members

We’re Hiring!

Please visit the Work With Us page to learn about available positions.

Principal Investigator

amutha-boominathan

Amutha Boominathan, PhD

Research Staff

BhavnaDixit-1a-o

Bhavna Dixit, MS (Research Associate II)

begelman

David Begelman, BS (Research Associate I)

Carly Truong_headshot

Carly Truong, BS (Research Technician)

Postbaccalaureate Fellows

Summer Scholars

Placeholder-Person-1

Jay-Miguel Fonticella (Class of 2022, Tufts University, BS)

Emily Wallace_headshot

Emily Wallace (Class of 2024, U Mich. BSE)

Lab Alumni

Research Staff

  • Jayanthi Vengalam (2012-2015) – now at Protagonist Therapeutics
  • Shon Vanhoozer (2014-2017)
  • Kathleen Powers (2015-2017) – now at Bristol Myers Squibb
  • Caitlin Lewis (2017-2021) – now at SENS Research Foundation CSO Team

Summer Scholars and Postbaccalaureate Fellows

Publications

Photos

Resources

Funding

To support our work please consider making a donation to SENS Research Foundation!

Thanks to our existing funders:

The Foster Foundation

Enhancing Innate Immune Surveillance of Senescent Cells

  • Research Info
  • Team Members
  • Publications
  • Resources
  • Photos
  • Funding
  • Research Info
  • Team Members
  • Publications
  • Resources
  • Photos
  • Funding

When normal cells lose their ability to replicate, they become senescent cells. Over time, senescent cells accumulate in aging tissues, spewing off a cocktail of inflammatory and growth factors, as well as enzymes that break down surrounding tissue and cause inflammation. This phenomenon is known as the “senescence-associated secretory phenotype” (SASP). Senescent cells – and the downstream impact of the SASP – are now implicated in a remarkable litany of the diseases of aging.

On a more encouraging note, multiple studies have now documented that “senolytic” drugs and gene therapies that destroy senescent cells exert sweeping rejuvenating effects in aging, both in laboratory animals and animal models of multiple diseases of aging. In theory, however, senolytic therapies shouldn’t be necessary. The body’s immune system is on continuous patrol against senescent cells: our natural killer (NK) cells recognize senescent cells as abnormal, bind to them, and release substances that trigger the senescent cells to self-destruct.

An SRF-donor-funded collaboration between Dr. Judith Campisi’s lab at the Buck Institute and the SRF Research Center seeks to discover why senescent cells accumulate with age, and what might we do to enhance immune surveillance and elimination of these cellular saboteurs?

Research Highlights:

The Campisi lab has recently published three papers describing the underlying mechanism of immune evasion by resistant senescent cells (Pereira et al., 2019, Munoz et al., 2019, and Kale et al., 2020). Dr. Campisi has found that a significant proportion of senescent cells manage to evade destruction, even by fresh NK cells. These ‘resistant’ cells escape immunosurveillance and accumulate in aging tissues. Senescent cells moreover shed decoy ligands binding to NK cell receptors; another aim of this work is to screen for more such ligands shed by senescent cells.

The Buck-SRF-RC collaboration is now seeking to drill further into the mechanism of senescent cell accumulation, and test interventions. At the SRF-RC, we are currently perfecting the method of co-culturing NK and senescent cells and controlling the killing process;  next, we will begin testing therapeutic interventions.

The SRF-RC scientists are also working for the first time with NK cells derived directly from aged human donors (rather than long-cultured lines of NK cells, or NK cells artificially “aged” by exposure to oxidative stress or extensive replication in culture, as has been done in the past). Using these cells will allow them to observe any direct effects of aging on NK cell senolytic activity.

Goals:

The primary goal of the laboratory is to find ways to avoid the accumulation with a focus on the immune system:

  • Reversing diminished immune surveillance
  • Use of NK cells to remove senescent cells

Goal 1: Natural killer cells are primary drivers of immune surveillance of senescent cells. This project involves isolation and characterization of age-dependent changes in the phenotypes of Natural Killer cells. This is to investigate if the age of subjects effects the ability of NK cells to eliminate senescent cells in vitro and in vivo.

Goal 2: We have identified several unique antigens expressed on the surface of senescent cells. The goal of this project is the targeted elimination of senescent cells by CAR-NK therapy. We are characterizing the surface an antigen on senescent cells and investigate if targeting this antigen can enhance NK cell-mediated clearance of senescent cells from patient-derived primary endothelial cells and fetal lung fibroblasts. The ultimate goal of the project is to demonstrate that the CAR-NK cells that are capable of eliminating senescent cells in ex vivo and mouse models.

Goal 3: Senescent cells are known to secrete a unique mixture of proinflammatory cytokines, chemokines and matrix modifying proteins called the SASP (Senescence Associated Secretory Phenotype). We have identified several SASP factors that may block immune surveillance by NK cells. Proof of principle experiments are currently being performed to investigate if selective removal of specific SASP factors can enhance immune surveillance of senescent cells. The long-term goal of this project is to develop therapeutic interventions based on removal of these SASP proteins for aging and related diseases.

Team Members

We’re Hiring!

Please visit the Work With Us page to learn about available positions.

Principal Investigator

Dr. Amit Sharma

Dr. Amit Sharma

Dr. Amit Sharma was awarded a Master’s degree in Biomedical Sciences from Delhi University, India.  He received his PhD in 2009 in Biotechnology from University of Pune for his work demonstrating microRNA regulation of cytokines involved in allergic inflammation in mice model. Dr. Sharma’s postdoctoral research at the Buck Institute, Novato California involved investigating novel molecular regulatory pathways involved in genotoxic stress and cellular senescence in invertebrate and mammalian models.

Dr. Sharma has recently joined SENS Research Foundation as Group Lead in the Senescence Immunology Research Group. His research focus involves studying how aging and senescence affects the immune system and his research group will also investigate strategies to harness the immune system in mitigating deleterious effects of senescent cells with translational focus.

Postdoctoral Fellow

Research Associate

Kristie_web

Kristie Kim
Identification and characterization of the surfaceome of senescent cells and development of CAR-NK cells to enhance immune surveillance

Postbaccalaureate Fellow

Gina Zhu (Postbaccalaureate Fellow, 2020-2021)
Identifying Novel Mechanisms to Enhance Natural Killer Cell Mediated Surveillance and Clearance of Senescent Cells

Summer Scholar

Chloe Amber Lindberg (Summer Scholar, 2021)
Investigating the effect of senescence-associated secretory phenotype (SASP) factors on NK cell function

Lab Alumni

Elena Fulton (Postbaccalaureate Fellow, 2019-2020)
Characterization of age dependent changes in peripheral NK cell phenotypes in humans

Mikayla Stabile (Summer Scholar, 2020)
Characterization of age dependent changes in peripheral NK cell phenotypes in humans

Publications

  • Kale A, Sharma A, Stolzing A, Desprez PY, Campisi J. Role of immune cells in the removal of deleterious senescent cells. Immun Ageing 2020 Jun 3;17:16. PubMed: 32518575.

Previous Publications by Dr. Sharma

Sharma A, Kumar M, Aich J, Hariharan M, Brahmachari S.K, Agrawal A and Ghosh B. Post-Transcriptional Regulation of Interleukin-10 Expression by hsa-miR-106a. Proc Natl Acad Sci U S A. 2009; 106: 5761-6. PMC 2659714

Sharma A, Kumar M, Ahmad T, Mabalirajan U, Aich J, Agrawal A and Ghosh B. Antagonism of mmu- mir-106a attenuates asthma features in allergic murine model. JAP, 2012.

Kumar M, Ahmad T, Sharma A, Mabalirajan U, Kulshreshtha A, Agrawal A, Ghosh B. Let-7 microRNA- mediated regulation of IL-13 and allergic airway inflammation. J Allergy Clin Immunol. 2011. PMID 21616524 

Kumar S, Sharma A and Madan B, Singhal V and Ghosh B. Isoliquiritigenin inhibits IkappaB kinase activity 
and ROS generation to block TNF-alpha induced expression of cell adhesion molecules on human 
endothelial cells. Biochem Pharmacol. 2007; 73:1602-12. 


Tanveer A, Mabalirajan U, Sharma A, Ghosh B, Agrawal A. Simvastatin Improves Epithelial Dysfunction 
and Airway Hyperresponsiveness: From ADMA to Asthma. Am J Respir Cell Mol Biol. 2011 Apr;44 (4):531- 
9. PMID 2055877

Ghosh B, Kumar S, Balwani S, Sharma A. Cell adhesion molecules: therapeutic targets for developing 
novel anti-inflammatory drugs. Advanced Biotech. 2005; 4:13-20. 


Sharma S, Sharma A, Kumar S, Sharma S.K. and Ghosh B. Association of TNF haplotypes with Asthma, 
Serum IgE levels and correlation with serum TNF-α levels. Am J Respir Cell Mol Biol. 2006; 35: 488-95.

Sharma A, Joseph Wu. MicroRNA Expression Profiling of Human Induced Pluripotent and Embryonic Stem Cells. Methods in molecular biology, a part in Springer Science. PMC 3638037

Sharma A, Diecke S, Zhang WY, Lan F, He C, Mordwinkin NM, Chua KF, Wu JC. The role of SIRT6 protein in aging and reprogramming of human induced pluripotent stem cells. J Biol Chem. 2013. PMID 23653361.

Lang S, Bose N, Wilson K, Brackman D, Hilsabeck T, Watson M, Beck J, Sharma A, Chen L, Killlilea D, Ho S, Kahn A, Giacomini K, Stoller M, Chi T, Kapahi P. A conserved role of the insulin-like signaling pathway in uric acid pathologies revealed in Drosophila melanogaster. bioRxiv 387779

Akagi K, Wilson K, Katewa SD, Ortega M, Simmons J, Kapuria S, Sharma A, Jasper H, Kapahi P. Dietary restriction improves intestinal cellular fitness to enhance gut barrier function and lifespan in D. melanogaster. PloS Genet. 2018 Nov 1; 14(11):e1007777. PMC6233930.

Sharma A, Akagi K, Pattavina B, Wilson KA, Nelson C, Watson M, Maksoud E, Ortega M, Brem R, Kapahi P. Musashi expression in intestinal stem cells attenuates radiation-induced decline in intestinal homeostasis and survival in Drosophila. Sci Reports. 2020 Nov 5;10(1):19080.

Full list of published work as found in My Bibliography:

https://www.ncbi.nlm.nih.gov/sites/myncbi/amit.sharma.2/bibliography/55316754/public/?sort=date&direction=ascending

Photos

Funding

To support our work please consider making a donation to SENS Research Foundation!

Thanks to our existing funders:

Identification and Targeting of Noncanonical Death Resistant Cells

SENS Research Foundation Research Center

Forever Healthy Foundation Fellowship in Rejuvenation Biotechnology

Fellow: Tesfahun Admasu

When cells age, they lose their proliferative capacity and stop dividing in a phenomenon called senescence. Cellular senescence decreases the regenerative capacity of cells and tissues.

Throughout the aging process, senescent cells accumulate and secrete a characteristic set of proteins, called the senescence-associated secretory phenotype (SASP). Although SASPs act as tumor suppressors and recruit immune cells to repair damage, they also mediate the deleterious effects of senescence and thus contribute to different pathologies, such as cancer, neurodegenerative diseases, and diabetes. Furthermore, SASPs can induce senescence in surrounding cells (called ‘secondary senescence’ or ‘paracrine senescence’), which can aggravate the effect. While there has been considerable research into the characteristics of primary senescent cells, not much is known about secondary senescent cells and how they are arise in vivo.

Project Goals

This project seeks to confirm the hypothesis that secondary senescent cells are different from primary senescent cells, and would therefore need a different senolytic to eradicate them. In addition, the project will study how SASP components mediate the spread of senescence. This work could provide us with a basis for new hypotheses of how to stop the spread, which in turn could lead to therapeutically viable interventions.

Research Highlights

In 2020, the project achieved a major breakthrough in successfully isolating secondary senescent cells using a senescent cell surface marker. This has never been done before and will allow a more in depth analysis of the cells and how they are different from primary senescent cells. The project has already performed RNA sequencing of the two cell types, finding many differentially expressed genes. Secondary senescent cells have a significantly altered phenotype. In the coming year we will focus on confirming the results and using them to optimize senolytics.

A Small Molecule Approach to Removal of Toxic Oxysterols as a Treatment For Atherosclerosis

This research program has successfully spun-out into a company! Visit the Underdog Pharmaceuticals, Inc. website for more information on their transformative approach to atherosclerosis.

SENS Research Foundation Research Center

Principal Investigator: Matthew O’Connor
Research TeamAmelia Anderson, Carolyn Barnes, Angielyn Campo, Anne Corwin, Sirish Narayanan

Many diseases of aging are driven in part by the accumulation of “junk inside cells:” stubborn, damaged waste products derived from the metabolic processes particular to specific cell types. The accumulation of these wastes disables the cell type in question and leads to their dysfunction; when, after decades of silent accrual, a critical number of these cells become dysfunctional, diseases of aging characteristic of that tissue erupt. For example, atherosclerotic lesions form when immune cells called macrophages take in 7-ketocholesterol (7-KC) and other damaged cholesterol byproducts in an effort to protect the arterial wall from their toxicity, only to ultimately fall prey to that same toxicity themselves. These macrophages – now dysfunctional “foam cells” – become immobilized in the arterial wall and spew off inflammatory molecules that in turn promote advanced atherosclerosis, heart attack, and stroke. In other organs, the accumulation of damaged molecules inside vulnerable cells drives Alzheimer’s and Parkinson’s diseases, as well as age-related macular degeneration.

Dr. O’Connor’s team have identified a family of small molecules that may be able to selectively remove toxic forms of cholesterol from early foam cells and other cells in the blood. If effective, these small molecules could serve as the basis for a groundbreaking therapy that would prevent and potentially reverse atherosclerosis and, possibly, heart failure.

Research Highlights:

A lead compound was identified following evaluation of data from human blood sample tests in conjunction with computer modeling to predict the likely behavior of rationally-designed molecules. Preliminary testing has indicated performance consistent with enhanced activity relative to the existing family of compounds: specifically, the candidate molecules exhibit selective targeting of toxic cholesterol byproducts, with significantly reduced affinity for native cholesterol. A patent application for this lead compound and others to be derived from it has now been submitted.

The team is now working to refine their original assay with the expectation that it will more accurately reflect the desired activity on toxic and native cholesterol, and also on an entirely different chemical approach to improved molecules derived from the original family. We are also working with a potential contract laboratory to test the absorption, circulation to tissues, and disposal of our lead candidate, and to perform toxicity assays. SRF has recently acquired a new robotic system to run the assay, which our in-house engineer, Anne Corwin, is now working to set up and program; the end result will be an increase in throughput that allows more rapid testing of more molecules.

Use of this Web site constitutes acceptance of the Terms of Use and Privacy Policy.

© 2021 SENS Research Foundation – ALL RIGHTS RESERVED

Thank you for Subscribing to the SENS Research Foundation Newsletter.

You can also

or

You can