Frontiers in fundamental translational immunology

T32 AI125209

Overview

The field of immunology has progressed at an astounding pace over the last 35 years. Accomplishments include the functional characterization of myriad myeloid and lymphoid subsets, the identification of critical immunomodulatory membrane-bound and secreted factors, insights into microbe sensing and the molecular pathogenesis of infectious agents (e.g. HIV), and the revelation of immune cell dynamics in vivo. Breakthrough technologies that have enabled many of these pathways of discovery include advances in optical imaging, genomics, proteomics and the generation of genetically modified animals. It is also noteworthy that many of the fundamental findings in immunology offered new insights and treatment approaches for human disease—perhaps most strikingly represented by recent advances in cancer immunotherapy. Thus, it is a most exciting and auspicious time to be training in immunology. It is truly a crosscutting field as immune cells and the mechanisms they employ interface with all organs and systems of the body, and when perturbed or misdirected can be a cause, consequence or contributor to acute and chronic disease.

The goal of this multi-thematic postdoctoral training program is to prepare trainees for an independent career in fundamental or translational immunology through a rigorous laboratory experience combined with enrichment activities and opportunities to participate in therapeutic development projects. Emphasis is placed on understanding the cellular and molecular basis of immune cell activation in the appropriate context of an immune response to infectious organisms and toxins, or the dysregulation that occurs in the context of chronic inflammation and autoimmunity. These fundamental insights provide the basis for novel therapeutic approaches in infectious disease, autoimmunity and cancer that will be tested in pre-clinical models

The program is designed to establish proficiency in molecular and cellular techniques, and the critical design and interpretation of relevant in vivo models. These goals are facilitated by the integration of state-of-the-art technological disciplines supporting the research activities. The program integrates four major themes: (1) adaptive immunity, (2) innate immunity, (3) mechanisms of immunity, and (4) systems immunobiology.

The training environment of the program is structured to engage trainees in active discussions of new scientific findings and ideas both within and between the themes. In addition, trainees will have the opportunity to learn about and utilize advanced technologies (chemical biology and drug discovery, genomics technologies, proteomics, bioinformatics and systems biology, structural biology and animal models of disease). Integral to this program is the participation of trainees in courses that leverage the unique translational environment of Sanford Burnham Prebys Medical Discovery Institute. Trainees will participate in advanced courses in drug discovery and bioinformatics that have proven highly successful within the education and training environment of the Institute. The hybrid nature of Sanford Burnham Prebys – academic science coupled with technological expertise in drug discovery – equips trainees with unique insights and mind-sets appropriate for the goals of the program.

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Program Director

Linda Bradley, Ph.D. headshotLinda Bradley, Ph.D.

Dr. Bradley is responsible for all managerial aspects of this training program. She works closely with the Steering Committee and the External Advisory Committee.

Application information

The Frontiers in Fundamental and Translational Immunology Program is an NIH-funded training program. This program accepts both PhD and PhD/MD postdoctoral researchers.
 

Citizenship requirements

Applicants must be United States citizens, noncitizen nationals or have been lawfully admitted for permanent residence by the time of their appointment.

Non-citizen nationals are people, who, although not citizens of the United States, owe permanent allegiance to the United States. They are generally people born in outlying territories of the United States (e.g., American Samoa and Swains Island). Individuals who have been lawfully admitted for permanent residence must have a currently valid Alien Registration Receipt Card (I-551) or other legal verification of such status.

Individuals on temporary or student visas are not eligible.
 

Prior Ruth L. Kirschstein-NRSA support

The National Research Service Award (now known as Ruth L. Kirschstein National Research Service Award) provides for a maximum of 3 years of post-doctoral funding. Since the CT2 program requires a minimum two-year, NRSA-eligible commitment, eligibility for the program requires that you have had no more than 1 year of prior NRSA post-doctoral support.
 

Faculty mentor

All applicants must identify a faculty mentor prior to having their application reviewed by the Steeering Committee. Please contact the mentor in whose laboratory you wish to complete your research prior to submitting your application. A letter from your mentor expressing interest in having you join his/her group is required to move your application forward.
 

Application requirements

If you would like to be considered for a training position, please identify one or more faculty mentors and complete and submit the following:

  1. Curriculum Vitae
  2. References: Please provide three references who will be able to provide Letters of Recommendation on your behalf.
  3. A one-page personal statement describing the following:
  • Why you are a good candidate for the fellowship.
  • Specific types of research that interest you and relevant experience.
  • What your goals will be during and after the fellowship.

Apply


For any questions regarding the application process, please email T32@sbpdiscovery.org.

Mentor information

The primary goal for the T32 trainees will be to advance their research project. Upon appointment to the Program, the trainee’s mentoring committee will be established. This mentoring committee will include the mentor and another faculty member (often a member of the Steering Committee) chosen to complement the expertise of the mentor and best suited to support the trainee’s research plan. After an initial meeting, each trainee will meet twice annually with the mentoring committee. The committee will review research progress and advise on additional training opportunities. It will also advise on advanced technology-based programs that would be advantageous to integrate in the trainee’s research project. When appropriate, the trainee will also be guided by the mentoring committee to obtain expert technical advice and assistance from other laboratories at SBP. The mentoring committee will advise on the preparation of fellowship proposals and, as the training period progresses, transitioning to an independent career. SBP’s OETIS facilitates a formal annual Individual Development Planning (IDP) process for all postdoctoral trainees that includes both research project and career components. As part of this training program, the IDP will be reviewed and revised by the trainee in collaboration with the mentoring committee and used as a tool for both the committee and the trainee to openly communicate about goals and achievements.

Clinical co-mentors: Although the value of scientific discovery cannot be overstated, it is especially important for researchers to be cognizant of the impact of their work on human health and unmet clinical needs. Therefore, we have a panel of colleagues to participate as clinical co-mentors. In consultation with the Steering Committee, trainees will be paired with a clinical mentor with shared interests. Clinical mentors have agreed to:

  1. Assist in outlining the research project as part of the Individual Development Plan (IDP).
  2. Participate in quarterly meetings with the mentor and trainee to provide input on the clinical relevance of the trainee’s project.
  3. Attend local retreats, seminars and/or group meetings when the trainee is presenting his/her work.
  4. Suggest how clinical relevance may be addressed via the use of clinical samples, public databases, etc., which could form the basis for active collaborations.
  5. Provide commentary on manuscript preparation.
     
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Mentor bios

Linda Bradley, Ph.D.

Programming the development and function of T cells in virus infections and cancer
Dr. Bradley’s research has for 25 years focused on understanding the development and function of subsets of T lymphocytes as well as their maintenance and regulation as memory cells. Research from the Bradley lab has contributed to the identification of the critical function of L-selectin in regulating homing of T cells, the essential contribution of OX40 on B cells in sustaining CD4 T cell responses, the key role of IL-7 in the survival and maintenance of memory CD4 T cells, and the novel function of CD44 in regulating Th1 cell and CD8 T memory generation. Studies of CD4 cells in autoimmune diabetes demonstrated that adaptive regulatory T cells could reverse hyperglycemia at disease onset and mediate long-term protection against reemergence of autoimmunity as memory cells. Studies on Th17 cells in this model revealed that these cells mediate pathogenicity via TNF-alpha production independently of either IL-17 or IFN-gamma Understanding adhesion mechanisms that regulate T cell migration, effector development, and memory has been a key underpinning of the research in the Bradley lab. New studies of chronic LCMV infection demonstrate that deficiency of CD44 enables early viral clearance by limiting stromal cell inhibition of T cell responses. Additional studies identified the selectin-ligand PSGL-1 (P-selectin glycoprotein-1) as a critical negative regulator of virus-specific CD8 and CD4 T cells that acts to attenuate TCR signaling. Importantly, deficiency of PSGL-1 prevents chronic infection with LCMV by promoting effector T cell generation and enabling viral clearance. Similarly, in a model of melanoma, PSGL-1 expression limits T cell anti-tumor responses.

Trainees will study how immunomodulation via these receptors impacts the outcomes of T cell antitumor responses using in vivo models, and will learn gene profiling and biochemical approaches to analyze transcriptional regulation and signaling pathways that become engaged. A key component of the project will be to use strategies to achieve immunomodulation using monoclonal antibodies, small molecules, and inducible conditional genetic deletion with newly developed mouse lines.
 

Sumit Chanda, Ph.D.

Host-pathogen interactions
Dr. Chanda’s research program leverages systems-based technologies to globally interrogate host–pathogen interactions. They focus on analyzing the host-requirements for RNA viruses, including IAV, DENV, WNV, and HIV-1, as well as investigating the cellular pathways that govern the innate immune response to challenge by these viruses, including RIG-I, TLRs, and cGAS. The Chanda lab employs OMICs tools including genome-wide RNAi/CRISPR screening, proteomics, chemical genomics, and next generation sequencing technologies, and have developed a computational pipeline to analyze the large datasets derived from these analyses, which enable us to rapidly translate global analyses into molecular and therapeutic insights.

Trainees will learn experimental and computational skills that will enable them to conduct and analyze large-scale experiments, as well as employ cell biological, biochemical, and virological techniques to provide mechanistic understanding of key nodes in the host-pathogen interface that underlie disease. The trainees will interact extensively with collaborators in San Diego (UCSD, The Scripps Research Institute, Salk), as well as nationally (UCSF, UCLA, Northwestern, MSSM) to conduct interdisciplinary, team-oriented research.
 

Ze’ev Ronai, Ph.D.

Rewired signaling in tumors and their microenvironment
Over the past two decades, Dr. Ronai’s research has focused on ubiquitin ligases (namely Siah1/2, RNF5 and RNF125) that are deregulated in cancer and play a fundamental role in essential cellular processes. The Ronai lab uses mouse genetic models as well as human tumor samples, augmented by relevant cell culture systems to study ubiquitin ligase mechanisms. They found that ubiquitin ligases Siah1/2 play a key role in regulating cellular hypoxia and are integral members of the unfolded protein response (UPR). In this capacity, Siah1/2 dictates cell death aptitude and determines the availability of HIF1a, the master regulator of the cellular hypoxia response. Siah inhibition attenuates tumor development and progression, as shown in prostate cancer and melanoma. Recent analyses points to the role of Siah1/2 in the tumor microenvironment, an aspect that is currently being explored and is expected to play a significant role in the immune system. Research based on structural information is bolstering the development of first in class inhibitors for Siah1/2. Work on the ubiquitin ligase RNF5 highlighted its importance in the control of autophagy and glutamine metabolism, with the latter being associated with tumor response to therapy. RNF5 has been implicated in the control of immune checkpoints, including upstream and downstream regulatory components of the STING network. Indeed, RNF5 KO animals are more resistant to melanoma development, which coincides with the level of CD4 and CD8 positive tumor infiltrating lymphocytes. Ongoing studies focus on the precise mechanisms underlying the regulation and function of RNF5 in tumor immunology and cancer, with the notion that RNF5 inhibitors may offer novel therapeutic modality to immune checkpoint-regulated tumors

Trainees have traditionally engaged in multiple disciplines, from basic biochemistry and cell biology to genetic models, allowing them to acquire new technologies and concepts as part of their developed project.


Guy Salvesen, Ph.D.

Pyroptosis, necroptosis, apoptosis and the control of innate immune responses
Research in Dr. Salvesen’s lab seeks to delineate the structure/activity/function algorithm as it applies to signaling by proteolytic enzyme networks in health and disease. The laboratory has broad interests in principles of proteolysis in humans, and takes multi-pronged approaches to research on proteases and their inhibitors. Using the techniques of protein chemistry, enzymology, crystallography, and genome editing, the laboratory analyzes the basic mechanisms utilized by proteases to promote cell death pathways, and devises inhibitors and probes to monitor them. Ongoing research is directed at dissecting the proteolytic components of the intracellular pathways that lead to regulated cell death, particularly inflammatory cell death. These programs contain a number of proteolytic steps that are essential for efficient execution of death pathways. Thus, the proteases of these pathways—the caspases and the neutrophil serine proteases— help maintain appropriate cell numbers, and are therefore implicated in a number of pathologic and physiologic conditions. The sum total of the proteases and their target substrates operating in a physiologic pathway defines global signaling events. Consequently, the identity of the substrate cleavages defines the proteases acting on them. Dr. Salvesen’s laboratory is developing proteomics-based methodologies, including selective protein labeling, multi-dimensional electrophoresis, and mass spectrometry techniques, to identify the products of proteolysis in vivo.

Trainees will study how proteolytic pathway components regulate cell death/survival decisions. During these studies, they will gain skills and expertise in molecular and cellular biology, enzymology, proteomics and protein biochemistry. In addition, they will use chemical tool synthesis and application as well as genome editing techniques to further dissect signaling pathways that involve specific limited proteolysis.
 

Carl Ware, Ph.D.

Design and development of immune-therapeutics for cancer, infectious and autoimmune diseases
Dr. Ware’s research focuses on the role of the TNF-related cytokines in human disease. His discoveries and characterization of the Lymphotoxin and LIGHT cytokine network revealed their importance as therapeutic targets in autoimmune disease, cancer and infectious diseases. Indeed, his research discoveries initiated the development of two novel therapeutics (Baminercept and anti-LIGHT) that are currently in clinical trials. Dr. Ware’s group uses biochemical (proteomics) approaches to define key elements in signaling pathways initiated by the LTβR and Herpes Entry Mediator (HVEM) and screens for chemical inhibitors in collaboration with the SBP CPCCG. Dr. Ware’s lab is developing protein-based agonists and antagonists for use in mouse disease models with conditional gene ablation, and viral infection and tumor models.

Trainees have the opportunity to design novel therapeutics with collaborators in the pharmaceutical industry that support Dr. Ware’s research. His lab actively participates in clinical trial development to evaluate new therapeutics. The postdoctoral training program in Dr. Ware’s laboratory provides the opportunity for trainees to be exposed to a full spectrum of techniques, from basic molecular biology, virology and immunology to therapeutic design and testing.
 

 

Cosimo Commisso, Ph.D.

Targeting metabolic pathways to enhance immunotherapy in pancreatic cancer.
 

Peter Adams, Ph.D.

Aging of the immune system as a cause of adult cancers
 

Maximiliano D’Angelo, Ph.D.

Nuclear Pore Complexes in the regulation of immune cell function
 

Randal J. Kaufman, Ph.D.

The role of protein misfolding in the endoplasmic reticulum and the unfolded protein responses in immunological disease
 

Robert Wechsler-Reya, Ph.D.

Overcoming immune evasion in pediatric brain tumors
 

Svasti Haricharan, Ph.D.

Understanding how DNA repair proteins alter the tumor microenvironment and anti-tumor immunity
 

Victoria Blaho, Ph.D.

Lipid signaling modulation of hematopoietic and immune cell responses to genotoxic stress

Trainee information

During the first year of the training program the primary goal for the T32 trainees will be to advance their research project. By the end of the calendar year, each trainee is expected to establish their mentoring committee. In addition to establishing the mentoring committee, each trainee will select a clinical co-mentor to further develop their research project to include a clinically-relevant component. Trainee progress for the first year of training will focus on advancing their research project and will be evaluated through (1) general evaluations from their preceptors and mentors; (2) performance and participation in program coursework and professional development activities; (3) research progress towards publications in scholarly journals or patents/licensing agreements indicative of research progress; and (4) participation in the broader immunology community through presentations at local, national, and/or international meetings.

 

Trainees

Jonathan J. Grist, Ph.D.
Mentor: Carl F. Ware, Ph.D.
Dr. Jonathan Grist is a second-year postdoctoral fellow.
Research project: Determining the mechanism of the lymphotoxin network within the CNS

Dr. Grist is working on two projects: understanding the role of the LTαβ-LTβR pathway in the CNS during MCMV infection and determining the mechanism of the HVEM-SALM5-PTPδ pathway. He has developed a mouse/rat chimeric LTβR monoclonal antibody and is increasing the production to study the LTβR pathway in the CNS. He has also been working to understand the binding and molecular signaling of SALM5 and HVEM. Dr. Grist is determining how the HVEM-SALM5 interaction/signaling is occurring in relation to the other HVEM-binding partners.
 

Jennifer Hope, Ph.D.
Mentor: Linda Bradley, Ph.D.
Research project: Role of PSGL-1 in T cell differentiation

PSGL-1 is a novel immune checkpoint regulator and PSGL-1-deficient T cells demonstrate increased effector responses in models of chronic viral infection and tumors. Dr. Hope previously determined that PSGL-1 expression in CD4 T cells influences T cell differentiation in a tumor model during the acute effector phase and at memory after viral infection. She also determined that there is a gene-dosage effect which influences T cell differentiation in vitro. In both CD4 and CD8 T cells, PSGL-1 expression is involved in regulating metabolism, as PSGL-1-deficient T cells have increased glycolysis upon activation. Finally, she used single-cell RNA sequencing of intra-tumoral T cells demonstrate that PSGL-1-deficient CD8 T cells have a unique transcriptional profile compared to wild-type CD8 T cells. Over the past year, Dr. Hope has expanded on these studies by evaluating impact of PSGL-1 on mitochondrial mass and potential in CD8 T cells, and expanded upon the metabolic studies from the first year including evaluation of the expression levels of key genes involved in T cell metabolism. Additionally, Dr. Hope has generated two novel melanoma tumor models that allow for the evaluation of T cell trafficking and the development of tumor-specific T cell memory.
 

Anshu P. Gounder, Ph.D.
Mentor: Sumit Chanda, Ph.D.
Dr. Gounder is a first-year postdoctoral fellow.
Research project and progress: Identification of cellular host factors that influence viral infection using a systems biology approach

Since joining the program, Dr. Gounder has provided technical and intellectual input on an ongoing project in the Chanda lab to determine the host and viral determinants that dictate influenza virus tropism in a diverse subset of human epithelial cells. Through the use of a heterokaryon cell system, Dr. Gounder was able to show that a host dependent factor was responsible for influenza infection in a permissive cell line and that this host factor was missing or lowly expresses in non-permissive cell lines. Dr. Gounder aims to develop a platform to enable the identification of cellular proteins whose localization is altered by viral (Dengue virus) infection. This approach will rely on an arrayed library of V5-tagged human ORFs and high content microscopy to accurately identify these events. This platform is scalable, accessible and can be adapted to a number of pathogens and/or perturbations, allowing a new approach to examine host-pathogen interactions.
 

Samuel Lin, Ph.D.