Chozha V. Rathinam, Dr. rer. nat.

1. Kode A, Mosialou I, Manavalan SJ, Rathinam CV, Friedman RA, Teruya-Feldstein J, Bhagat G, Berman E, Kousteni S. FoxO1-dependent induction of acute myeloid leukemia by osteoblasts in mice. Leukemia 30,1-13 (2016).

2. De A, Dainichi T, Rathinam CV and Ghosh S.The deubiquitinase activity of A20 is dispensable for NF-κB signaling. EMBO Reports15, 775-83 (2014).

3. Kode A, Manavalan JS, Mosialou I, Bhagat G, Rathinam CV, Luo N, Khiabanian H, Lee A, Murty VV, Friedman R, Brum A, Park D, Galili N, Mukherjee S, Teruya-Feldstein J, Raza A, Rabadan R, Berman E and Kousteni S. Leukaemogenesis induced by an activating β-catenin mutation in osteoblasts. Nature 506, 240-4 (2014).

4. Baldzizhar R, Fedorchuk C, Jha M, Rathinam CV, Henegariu O and Czyzyk J. Anti-serpin antibody mediated regulation of proteases in autoimmune diabetes. The Journal  of Biological Chemistry 288, 1612-9 (2013).

5. Kriegel MA, Rathinam CV and Flavell RA.Pancreatic Islet expression of Chemokine CCL2 suppresses autoimmune diabetes via tolerogenic CD11C+CD11B+ Dendritic Cells. Proc Natl Acad Sci USA 109, 3457-62 (2012).

6. Ahmed N, Zeng M, Sinha I, Polin L, Wei WZ, Rathinam CV, Flavell R, Massoumi R and Venuprasad K. The E3 Ligase Itch and Deubiquitinase Cyld act together to regulate Tak1 and Inflammation. Nature Immunology, 12, 1176-83 (2011).

7. Rathinam CV, PoueymirouWT, RojasJ, MurphyAJ, ValenzuelaDM, YancopoulosGD, Rongvaux A, EynonEE, Manz  MG and FlavellRA. Efficient differentiation and functions of human macrophages in the humanized M-CSF mice. Blood 118, 3119-28 (2011).

8. Strowig T, Rongvaux A, Rathinam CV, Eynon EE, Manz MG and Flavell RA. Transgenic expression of human SIRPa improves the engraftment of human cells in Rag2-/- common gC-/- mice. Proc Natl Acad Sci USA 108, 13218-23 (2011).

9. Kamanaka M, Zenewicz LA, Huber S, Gagliani N, Rathinam CV,  O’ Connor W, Wan YY, Nakae S, Iwakura Y, Hao L and Flavell R. CD45RB^lo CD4 T cells are controlled directly by IL-10 and cause IL-22 dependent colitis. The Journal of Experimental Medicine 208,1027-40 (2011).

10. Rongvaux A, Willinger T, Takizawa H, Rathinam CV, Wojtek A, Murphy AJ, Valenzuela DM, Yancopoulos GD, Eynon EE, Stevens S, Manz MG and Flavell RA. Human thrombopoietin Knock-in mice efficiently support human hematopoietic stem and progenitor cells. Proc Natl Acad Sci USA 108, 2378-83 (2011).

11.Rathinam CV and Flavell R. c-Cbl deficiency leads to diminished lymphocyte development and functions. Proc Natl Acad Sci USA107, 8316-21 (2010).

12.RathinamCV*, KriegelM* and FlavellR. E3 Ubiquitin Ligase GRAIL Controls Primary T Cell Activation and Oral Tolerance. Proc Natl Acad Sci USA 106, 16770-5 (2009). *Equal contribution & Indicated First

13. Legrand N, Ploss A, Balling R, Becker PD, Borsotti C, Brezillon N, Debarry J, de Jong Y, Deng H, Di Santo JP, Eisenbarth S, Eynon E, Flavell RA, Guzman CA, Huntington ND, Kremsdorf D, Manns MP, Manz MG, Mention JJ, Ott M, Rathinam C, Rice CM, Rongvaux A, Stevens S, Spits H, Strick-Marchand H, Takizawa H, van Lent AU, Wang C, Weijer K, Willinger T, Ziegler P. Humanized mice for modeling human infectious disease: challenges, progress, and outlook Cell Host Microbe 6, 5-9  (2009)

14.Rathinam CV*, Schwermann J*, Schubert M*, Schumacher S, Noyan F, Koseki H,  Kotlyarov A, Klein C, Gaestel M. MAPKAP Kinase MK2 maintains self-renewal capacity of hematopoietic stem cells. The EMBO Journal 28, 1392-406 (2009). *Equal contribution & Indicated First

15. Templin C, Kotlarz D, Rathinam CV, Rudolph C, Schätzlein S, Ramireddy K,    Rudolph KL, Schlegelberger B, Klein C, Drexler H.Establishment of immortalized multipotent hematopoietic progenitor cell lines by retroviral-mediated gene transfer of beta-catenin. Experimental Hematology 36, 204-15 (2008).

16.Rathinam CV and Flavell R. The hematopoiesis paradigm: clarity or ambiguity ? Blood 112, 3534-5 (2008).

17. Ju Z, Jiang H, Jaworski M, Rathinam CV, Gompf A, Klein C, Trumpp A, and Rudolph KL. Telomere dysfunction induces environmental alterations limiting hematopoietic stem cell function and engraftment. Nature Medicine13, 742-747 (2007).

18. Klein C, Grudzien M, Appaswamy G, Germeshausen M, Sandrock I, Schäffer AA, Rathinam CV, Boztug K, Schwinzer B, Rezaei N, Bohn G, Melin M, Carlsson G, Fadeel B, Dahl N, Palmblad J, Henter JI, Zeidler C, Grimbacher B, Welte K. Hax1 deficeincy causes autosomal recessive severe congenital neutropenia (Kostmann disease). Nature Genetics 39, 86-92 (2007).

19. Bohn G, Allroth A, Brandes G, Thiel J, Glocker E, Schaffer AA, Rathinam CV, Taub N, Teis D, Zeidler C, Dewey RA, Geffers R, Buer J, Huber LA, Welte K, Grimbacher B, Klein C. A novel human primary immunodeficiency syndrome caused by deficiency of the endosomal adaptor protein p14. Nature Medicine 13, 38-45 (2007).

20. Jung J, Bohn G, Allroth A, Boztug K, Brandes G, Sandrock I, Schaffer AA, Rathinam CV, Kollner I, Beger C, Schilke R, Welte K, Grimbacher B, Klein C. Identification of a homozygous deletion in the AP3B1 gene causing Hermansky-Pudlak syndrome, type 2. Blood 108, 362-9 (2006).

21.Rathinam CV, Sauer M, Ghosh A, Rudolph C, Hegazy A, Schlegelberger B, Welte K, Klein C. Generation and characterisation of a novel hematopoietic progenitor cell line with DC differentiation potential. Leukemia 20, 870-6 (2006).

22. Saravanamuthu SS, von Gotz F, Salunkhe P,  Rathinam CV, Geffers R, Buer J,Tummler B, Steinmetz I.Evidence for polyadenylated mRNA in Pseudomonas aeruginosa. Journal of Bacteriology 186, 7015-8 (2004).

23. Krishnamurthy KVK , Krishnaraj R, Rathinam CV, Christopher S. The Programme Of Cell Death In Plants and Animals -A Comparison. Current Science 79 (2000).

The major lines of our current investigation include:

Inflammatory Signals as Key Regulators of Hematopoiesis:  The role of infection and inflammation in the control of hematopoiesis has gained a lot of attention in the recent years. While it was believed that only lineage committed progenitors were involved in sensing and in responding to infections, it is now evident that  hematopoietic stem cells (HSCs) are directly involved in the primary response of both acute and chronic infections.  The direct response of HSCs to an immune insult might be a key determinant in the clearance of the pathogen, since HSCs can dictate cell fate decisions and can preferentially differentiate into a particular hematopoietic lineage, in order to clear the pathogen.While previous studies have elegantly and unequivocally demonstrated the significance of inflammatory signals in determining the outcome of hematopoiesis, molecular mechanisms through which inflammatory signals governs HSC proliferation and differentiation remain largely unknown. A series of recent studies (Nakagawa MM, Cell reports, 2018; Nakagawa MM, Frontiers in Cell and Developmental Biology, 2018; Nakagawa MM, Stem Cell Research, 2018;Nakagawa MM, Scientific Reports, 2019)  from our laboratory indicated that decontrolled inflammation (through either a deficiency of an ubiquitin editing enzyme–A20 or constitutive activation of canonical NFkB pathway) results in pancytopenia, myeloproliferation, bone marrow failure and premature death. We are currently investigating the molecular machinery through which inflammatory cytokines drive pathological processes.

Neuroinflammation-Induced Immune Dysfunction: Traumatic brain injury (TBI) is one of the major causes of morbidity and disability worldwide.  Approximately, 1.7 million people are afflicted by TBI every year and contributes to 30 % of all injury related deaths.  The annual cost of treatment, within the United States, for patients with TBI is ~$60 billion. TBI involves a spectrum of pathoanatomical subtypes and induces complex pathophysiological pathways. In addition to causing severe trauma in the brain, TBI initiates a cascade of cellular, molecular, biochemical  and immunological events that are referred to as “secondary injury”.  Indeed, clinical outcome of TBI is often determined by the nature and severity of both primary and secondary injuries. Neuroinflammation is an adverse outcome and a key manipulable aspect of secondary injury following TBI.  While the clinical significance of tightly controlled neuroinflammation has begun to unfold, the pathophysiological consequences of TBI mediated neuroinflammation remain incompletely understood. Inadequate knowledge on systemic defects caused by TBI is believed to be  one of the major challenges in designing effective therapies. Recent research from our laboratory has discovered major immunodeficiencies caused by TBI-induced neuroinflammation.   We are currently identifying the cellular  and molecular players that participate in and control the neuro-immune crosstalk. We believe that  our studies would provide insights on novel therapeutic strategies towards treatment of patients suffering from TBI.

Molecular Control of Dendritic Cells : Dendritic cells (DCs) are essential to initiate and dictate both innate and adaptive immune responses. In particular, DCs are essential for antigen presentation and initiation of protective T cell responses. DCs are located throughout the body and form a sophisticated and complex network that allows them to communicate with different population of lymphocytes. Intensive research in the past several years enriched our knowledge on the functional roles of distinct DC subsets in steady and pathologic states. However, molecular mechanisms that drive differentiation of hematopoietic progenitors into the DC lineage remain largely unknown. One of the major interests of the Rathinam lab is to identify novel transcriptional targets and molecular drivers of DC development and functions, which may allow to engineer DCs for immunomodulation and targeted vaccine approaches.  Through a spectrum of gene specific knock-out and transgenic mouse models and selective ablation of the candidate genes at distinct stages of DC development, we are currently investigating the involvement of key transcription factors, E3-ubiquitin-ligases and signal transduction pathways in the differentiation and antigen presentation functions of DCs.

We currently looking for highly motivated students and postdoctoral fellows. 

2015  BD Immunology Award

2014  New Innovator Award, Leukemia Research Foundation, USA

2007  Best Ph.D thesis work award, University of Tubingen, Germany

2005  ASH Travel Award, American Society  of Hematology, USA

2000  Best Research Presentation Award, SASTRA University, India

Current:

2017-2022       1R01HL132194-01 (Role: Principal Investigator)

                          NF-kB signaling in the control of Hematopoiesis

                          National Institutes of Health/National Heart Lung Blood Institute  (NHLBI)

2015-               Role: Principal Investigator

                         "Itchy" basophils of the Immune System

                         BD Biosciences Immunology Grant

Completed:

2014-2015      Role: Principal Investigator

                        Role of A20 in the restriction of myeloid Leukemia

                        Leukemia Research Foundation

2010-2011     Role: Lead Investigator

                       Genetic & Molecular Control of E3 Ubiquitin Ligases in Stem Differentiation

                       National Institues of Health (NCRR),  5P20RR018757-09