Daniel Goldstein - US grants

DESCRIPTION: (adapted from applicant's abstract) Dr. Daniel Goldstein has submitted a Mentored Clinical Scientist Development Award (K08) application. Dr. Goldstein is training in Cardiovascular Medicine at the University of Alabama at Birmingham (UAB) and will become an Instructor in the Department of Medicine in July 2000. His career objective is to become a physician-scientist caring for cardiac transplant recipients with a research emphasis in transplantation immunology. His proposal will investigate the molecular mechanisms of donor spleen cell induced transplantation tolerance. Since failed solid organ transplantation is largely due to transplant rejection and the side effects of chronic immunosuppression agents, there is a need to develop protocols that can induce transplantation tolerance. The hypothesis of the research plan is that donor splenic natural killer cells secrete transforming growth factor beta inducing graft reactive cells to undergo apoptosis by a tumor necrosis factor dependent mechanism thus prolonging transplant survival. This hypothesis will be tested in a murine skin transplant model through use of mice with targeted mutations and by infusion of defined spleen cell subpopulations. Further, in vitro allogeneic cytotoxicity studies will be performed using blocking antibodies, and viral transduction of donor spleen cells. The University of Alabama has considerable expertise in experimental immunology and transplantation. The Department of Medicine will ensure that Dr Goldstein receives adequate space and time to devote 80% of his effort towards the research proposal. The career development program, mentor and didactic courses are designed to allow Dr. Goldstein to become an independent investigator by the end of the award period.

[unreadable] DESCRIPTION (provided by applicant): Clinical studies have shown that the elderly are susceptible to multiple disease processes including cancer, autoimmunity and infections, implying that aging leads to aberrant immune function. However, the mechanisms by which aging impairs immunity remain obscure. Due to the rapid expansion of the elderly subpopulation in Western countries, and the heavy burden such growth will pose on our health-care resources, there is an urgent need both for more research into immunity and aging and for the development of more effective therapies for treating the elderly. Our preliminary data demonstrates that primary T cell dependent immunity is impaired in aged vs. young T cells due to defective up-regulation of the ICOS costimulatory receptor. Hence, this proposal will test the hypothesis that restoring costimulatory receptor up-regulation during a primary immune response will enhance immune memory generation in aged hosts and restore protective immune memory. Specifically, we will examine if defective up-regulation of costimulatory receptors is responsible for impaired primary anti-viral immunity in aged murine hosts (aim 1). We will then investigate if adjuvant therapy will restore the up-regulation of costimulatory receptors on viral specific T cells and rescue the primary immmune response in the aged host (aim 2). Finally, we will examine if recovered primary immunity leads to preserved immune memory responses in the aged host (aim 3). As a result, this proposal will provide essential mechanistic information as to whether immune memory can be enhanced in the aged host and will help accelerate clinically relevant protocols for enhancing the efficacy of vaccinations in the elderly. Dr. Goldstein is a highly promising physician scientist who has already published in high-impact journals in transplant immunology. He has switched his focus to immunosenescence and is committed to exploring the basic mechanisms of aging and immunity. Yale University has a long and outstanding record in fostering the careers of young physician scientists. The additional mentored support offered by this RFA is critical for Dr. Goldstein to develop expertise in the biology of aging and how it relates to immunosenescence, ensuring that Dr. Goldstein will become a leading independent physician scientist in this area. [unreadable] [unreadable] [unreadable]

This research in cultural anthropology studies the effect of personal insecurity on people's attitudes toward and tolerance of democratic values and human rights in a democratizing context. The central hypothesis is that insecurity and lack of access to a democratic rule of law create conditions that threaten the preservation of democracy in societies recently transformed from authoritarian governance. The research hypothesizes that personal security correlates with tolerance for basic democratic principles and human rights, and that urban residents of Cochabamba, Bolivia who lack personal security are more likely to adopt violent remedies to address their situations than are those who have access to other ways to ensure security. Using ethnographic methods of investigation (including participant-observation, focus groups, and personal interviews), the research compares the responses of residents of three different communities in Cochabamba, all of whom lack access to official justice, but who have compensated for this lack in three different ways: by employing private security firms; by maintaining a system of community justice brought through migration from the countryside; and by resorting to vigilante violence. It hypothesizes that in the two communities that have developed non-violent alternatives to compensate for the lack of official policing and judicial services, tolerance for democracy and human rights will be greater than in the community that employs vigilante violence as a crime-control measure.
Broader Impacts: The new knowledge produced by this research will be useful to governments and planners concerned with improving the democratic transition, to support not only formal democratic measures like elections but the implementation of a rule of law in newly democratic societies, and so reduce the violence and insecurity with which so many of the world's people now live.

Innate immunity via Toll Like Receptors (TLRs) is the first line of defense against microbial invasion and is essential for pathogen detection. Our preliminary data, using experimental murine systems, also demonstrates that TLR dependent immunity is important for alloimmune responses by allowing the maximal function of dendritic cells (DCs), specifically the production of proinflammatory cytokines that subsequently initiate TH1 alloimmunity. Although these effects are critical for the rejection of minor mismatched skin allografts they are not essential for the rejection of fully allogeneic skin and cardiac allografts. However, the role of innate immunity in transplantation tolerance remains unexplored. Since a prior report, using non-transplant in vitro models, demonstrated that T regulatory cell (T reg) function changes in the presence of TLR stimulated DCs, our preliminary data investigate the impact of innate immunity on transplantation tolerance and show that absence of MyD88, an important TLR signal adaptor, is critical for tolerance induction. We provide evidence that this occurs via a regulatory mechanism that is associated with increased numbers of CD4+CD25+ T cells and a reduced proinflammatory milieu. Therefore, this proposal will employ a murine experimental transplant model and will examine the mechanisms by which defective innate immunity facilitates transplantation tolerance. Aim 1 of this proposal will examine whether the absence of MyD88 operates in synergy with the tolerance protocol (costimulatory blockade), tipping the balance towards tolerance rather than immunity, by increasing the generation and function of T regs. Aim 2 will investigate whether MyD88 deficiency, by reducing the proinflammatory cytokine environment, increases T effector susceptibility to regulation leading to tolerance induction. Therefore, this proposal will critically address whether an absence of innate MyD88 signaling promotes transplantation tolerance, a previously unexplored concept in the field of transplantation. The information generated will support a new paradigm in the field of transplantation and has the potential to provide future therapeutics translatable to human allograft transplantation and autoimmunity (e.g., MyD88 blockade at the time of tolerance induction).

[unreadable] DESCRIPTION (provided by applicant): Clinical studies have shown that older persons are more susceptible to multiple diseases including cancer, autoimmunity and infections and manifest an impaired response to vaccinations. This implies that the elderly have aberrant immune responses. Although several earlier studies have shown that aging impairs T cell function, most of these studies were performed prior to the appreciation of the innate arm of the immune system. The Toll like receptors (TLRs) are critical innate immune receptors on dendritic cells (DCs), which represent the most powerful antigen presenting cells that respond to specific microbial motifs. Upon TLR ligation DCs are essential for effective priming of both na'i've CD4+ and CD8+ T cells. However, the impact of aging on DC-dependent immune function is unclear. It is critical to answer this fundamental question if we are to develop effective therapies to improve immune function in older people. The urgency of this issue is rising since the elderly subpopulation in western countries is rapidly increasing and posing a heavy burden on our health care resources. Our preliminary data using experimental allogeneic murine models provide novel evidence that TLR immunity in myeloid DCs remains preserved with aging in response to a broad range of TLR agonists. Therefore, in this proposal, we are in a strong position to test the hypothesis that aging specifically impairs adaptive intrinsic CD8+ T cell immune responses to viral infection with preserved innate DC-dependent TLR immune priming. Specifically, we will employ a murine LCMV infection model to discern if aging impairs either innate DC-dependent TLR immune priming or adaptive intrinsic CD8+ anti-viral immunity (aims 1 and 2). In aim 3 we will test the hypothesis that specific TLR agonists augment the proinflammatory cytokine milieu and boost primary anti-viral CD8+ T immunity in the aged host. In selected cases we will use alternate pathogens to examine if our findings are applicable to other viral infections. Therefore, this proposal will provide critical, fundamental information as to whether aging impairs innate DC- dependent TLR immunity or adaptive intrinsic CD8+ T cell immune responses during viral infection and will provide insights as to whether TLR agonists can act as adjuvants and restore primary immunity in the aged host. The resulting information will be essential to accelerate clinically relevant therapeutic protocols that will augment the immune response and help restore health in older people. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Clinical Studies have demonstrated that aging increases the risk of atherosclerosis. As the number of older people continues to grow, morbidity from atherosclerosis in older adults will pose a heavy burden on our health care resources. There has been a growing appreciation that inflammation is a key pathopysiological mechanism that underpins the development of atherosclerosis. Importantly, both experimental and clinical studies provide evidence that microbial infections, including viruses, exacerbate the development of atherosclerosis. Prior studies have demonstrated that aging impairs immune function and leads to a reduced ability to clear viruses. Data from our laboratory, supported by a recently acquired R01 (R01AG028082), has demonstrated that aging impairs the function of plasmacytoid DCs (pDCs), critical innate sensors of viral infection. This K02 application will complement the currently funded R01 and will examine how aging accelerates the atherosclerotic process; in particular, it will elucidate the mechanisms by which viral infections exacerbate atherosclerosis with aging. Importantly, we will examine if TLR-based vaccines protect against subsequent viral infection with aging and ameliorate virus-exacerbated atherosclerosis. In testing these hypotheses, we will collaborate with two senior vascular biologists, Drs. Sessa and Tellides. Thus, this K02 proposal will allow me to focus on my research program and develop new scientific collaborations that will be instrumental to leading a future program project on the effects of aging on cardiovascular diseases. Relevance (see instructions): The number of older people in our society will continue to grow. As older people will have an increased probability of developing heart attacks and strokes, it will be imperative to understand how aging leads to increased cardiovascular diseases. This proposal will investigate mechanisms by which aging leads to cardiovascular diseases using murine experimental models.

Activation of the innate immune system impairs transplant tolerance induction. Our prior work supported by the last cycle of the award, demonstrates that signaling via MyD88, an adaptor protein downstream of most Toll like receptors, prevents transplant tolerance induction. Although we determined that synergy between IL-6 and TNF-a is critical for this effect, we know neither the identity of the MyD88 expressing cell that mediates transplant tolerance resistance nor the innate activators that are sensed by this cell. It will be critical to ascertain this information for novel therapies that inhibit the innate immune response at the site of injury, i.e., within the transplant. Here we hypothesize that MyD88 expressing CD11c+ dendritic cell sense innate immune ligands, including hyaluronan to prevent transplant tolerance induction. In this proposal we will discern the nature of the innate immune ligands and the identity of the cell that responds to these ligands to induce transplant tolerance resistance. Specifically, we will use innovative genetic murine approaches to examine if MyD88 expressing CD11c+DCs are both necessary and sufficient to induce transplant tolerance resistance. In addition, we will employ both pharmacological and novel genetic approaches to deplete hyaluronan within allografts, in order to examine if hyaluronan is a critical innate ligand that induces transplant tolerance resistance. Finally, we will employ proteomic approaches to determine the identity of novel innate ligands from the lysates of immunogenic grafts that resist transplant tolerance and examine if such ligands activate CD11c+DCs via a MyD88-dependent pathway. We will also determine whether any discovered ligands are less evident in organs such as hearts that are prone to tolerance induction. Our proposed study will provide critical information concerning the cellular and molecular mechanism by which the innate immune system impairs transplant tolerance induction. Such fundamental information will help guide future endeavors at inducing transplant tolerance in the clinic, ultimately leading to novel therapies and treatment options for patients.

Rutgers University doctoral student, Assaf Harel, under the guidance of Dr. Daniel Goldstein, will undertake research on concepts of time and local politics in contemporary pioneer settlements. Pioneer settlement is a source of both opportunity and conflict in the contemporary world. How settlers assign meaning to the past, the present, and the future appears to be significant for predicting the potential for territorial disputes. The research will be carried out among two ideologically different Jewish settlement blocs in the West Bank. Through the use of qualitative and ethnographic methods that include interviews, archival research and participant observation, the researcher will investigate (1) how different groups of settlers assign meaning to events in time; (2) how they view their own capacity to influence the flow of history, and (3) how these conceptions of time relate to ideology as well as to settlement-making practices.

The research is important because it may offer a lens into the local-level roots of seemingly intractable conflicts in many parts of the world today. Findings from the research also will contribute to social scientific understanding of the relations between time and space and thus will deepen understanding of temporal dimensions of territorial disputes. Funding this research also supports the education of a social scientist.

DESCRIPTION (provided by applicant): Viral infections induce higher morbidity and mortality in older people than in younger individuals. Based on both experimental and clinical studies, this disease burden is thought to be due to declining immune responses. However, our published work supported by the last cycle of the award challenges this paradigm as we found that older mice exhibit dysregulated immune responses during viral infection that induce immune pathology. This dysregulation consists of exaggerated IL-17 responses produced by natural killer T (NKT) cells, innate immune lymphocytes that respond rapidly to pathogens, coupled to defective type I interferon (IFN) responses by plasmacytoid dentritic cells (pDCs), sentinel immune cells that aid viral clearance. This defective viral clearance synergizes with the age-elevated IL-17 responses leading to severe liver inflammation and death. During non-lethal systemic viral infections, exaggerated inflammatory responses (i.e., IL-6 production) by NKT-cells coupled with defective type I IFN responses by pDCs induce an inflammatory environment that skews adaptive immune CD4+ T cells to an IL-17 producing phenotype. We have also observed the age-elevated IL-17 response coupled to defective type I IFNs in other viral infections such as in localized influenza lung infections. Here, we propose to study the underlying cellular and molecular mechanisms for dysregulation of immune responses with aging by using murine models to determine 1) if exaggerated inflammatory responses by NKT cells coupled to defective pDC responses are critical for the generation of IL-17 anti-viral CD4+ T cells during systemic herpes viral infections with aging; and 2) whether exaggerated IL-17 responses by aged NKT cells coupled with impaired type I IFN responses by pDCs also induce immune pathology during influenza viral lung infection. Our work will greatly differ from mainstream research in the field and may lead to novel anti-inflammatory therapies to improve immunity to viral infections with aging.

DESCRIPTION (provided by applicant): Components of the innate immune system can contribute to impairment of long term allograft tolerance. However, the molecular activators that trigger the innate immune system to initiate allograft rejection are elusive. Our prior work demonstrates that signaling via MyD88 an adaptor protein downstream of most Toll like receptors on innate immune cells, prevents transplant tolerance. In addition, we have preliminary evidence to suggest that hyaluranan (HA) is an innate ligand that activates the MyD88 inflammatory pathway to initiate allograft rejection and transplant tolerance resistance. We hypothesize that differential HA expression levels in various tissues may explain why some organs, such as the skin, exhibit impaired transplant tolerance, while other tissues, e.g. cardiac allografts, are susceptible to tolerance induction. Deciphering such differences could inform on the generation of novel therapies to inhibit the innate immune response at the site of injury (i.e., within the allograft). In Aim 1 of this proposal, we will employ pharmacological approaches to block HA activity in experimental models of acute transplant rejection and transplantation tolerance for which MyD88 signaling is critical for graft rejection. In Aim 2, we will generate mice in which HA is inducibly deleted within skin allografts. This mouse model will be a useful resource for future experiments to determine if HA mediates MyD88 dependent rejection of skin allografts. We will complement this approach by generating mice in which HA is over-expressed within cardiac tissue. This will allow us to examine whether HA over-expression is sufficient to impair transplant tolerance of cardiac allografts. Hence, this proposal will generate novel reagents to examine the role of HA in acute graft rejection and transplant tolerance induction. Moreover, these resources would also impact other models of inflammation for which HA may play a major role. PUBLIC HEALTH RELEVANCE: Both experimental and clinical studies have revealed that the innate immune system contributes to acute rejection of organ allografts and transplant tolerance resistance. However, we do not know the nature of the substances that activate the innate system after organ transplantation. This proposal will examine whether a putative innate ligand, hyaluronan, is critical for acute allograft rejection and transplant tolerance resistance through pharmacological approaches and through generation of novel mice with modulated hyaluronan expression.

Dr. Daniel Goldstein (Rutgers University) will study how and why Latino migrants use the U.S. legal system to prosecute workplace disputes. Focusing on several study communities in central New Jersey, the research considers the ways in which migrants who claim to have suffered from mistreatment or injury in the workplace become active users of the law and the U.S. justice system. The project asks how Latino migrants seek the help of lawyers and non-profit legal advocacy groups; educate themselves about the law and appeal to its protections; enter the court system and argue their cases; and articulate rights claims. The project also studies the role that legal-aid organizations play in facilitating migrants' understandings of and access to the legal system.

The research uses an ethnographic research methodology, employing a research team that includes trained local research assistants. Through participant-observation followed by semi-structured individual and focus group interviewing, the team will study the vulnerabilities and behaviors of migrants who have suffered workplace abuses. Additionally, through volunteer work in a local migrant legal-aid organization, the research team will study how these organizations facilitate migrants encounters with the legal system.

The proposed research is very timely and important given the current fluidity in the U.S. around immigration issues, with Latino migrants potentially emerging into a new era of visibility, advocacy, and action in this country. The research will shed new light on the realities facing migrants in the U.S. with a special focus on workplace problems, and the legal remedies migrants pursue in response. By training and deploying a team of community-based researchers, this project will build capacity in local migrant communities, preparing people for future educational opportunities and employment in social science research.

DESCRIPTION (provided by applicant): Solid organ transplantation is an effective therapy for several end-stage diseases. Its success has been driven by the development of immune suppressive medications that impair the immune response to the transplant. To avoid transplant rejection, combinations of these medications must be taken regularly. However, these medications induce undesirable side effects, such as hypertension and diabetes, as well as increased susceptibility to opportunistic infections and cancer. The development of drug delivery platforms that effectively deliver combination immune suppressants while avoiding drug-induced side effects would be transformative for the solid organ transplant field. We hypothesize that co-encapsulation of the commonly employed immune suppressive medications rapamycin and mycophenolic acid into FDA- approved poly(lactic-co-glycolic acid) (PLGA) nanoparticles will prolong allograft survival and avoid the toxic side effects of the soluble administered drugs. In addition, one of our recent studies demonstrated that nanoparticles encapsulated with mycophenolic acid target dendritic cells and induce the upregulation of PD-L1, a negative costimulatory ligand, on these cells. As soluble administered rapamycin is known to impair the upregulation of activating costimulatory ligands on dendritic cells, we also hypothesize that co- encapsulation of rapamycin and mycophenolic acid will induce a pro immune tolerant phenotype in dendritic cells and enhance the development of transplant tolerance. To investigate whether combined encapsulation of rapamycin and mycophenolic acid within nanoparticles prolongs allograft survival, avoids toxic drug side effects and enhances the development of transplant tolerance, we will employ experimental murine transplant models after proof-of-concept studies have been completed in vitro, and both agents have been optimized for NP drug delivery. We expect that the anticipated results of our study will lay the foundation to a ground-breaking clinical study to deliver combination immune suppressants to organ transplant recipients via nanoparticles, which would be transformative to the solid organ transplant field.

? DESCRIPTION (provided by applicant): Cardiovascular diseases are posing an increasing threat to the health of older people. However, how aging impacts cardiovascular disease remains unclear. A highly collaborative environment is required to unravel the complexities of this problem. The goal of this leadership award is to develop a world-class center on aging and cardiovascular diseases at Yale School of Medicine to foster highly productive research collaborations and to educate and train the next generation of leaders in this important field. The proposed Center would be the first of its kind in the nation and will be led by Dr. Goldstein, an established physician-scientist and cardiologist who investigates how aging impacts inflammation. The Center's specific goals will be addressed in the following three aims: (1) to bring together established investigators to broadly examine how increased inflammation with aging enhances cardiovascular diseases employing both pre-clinical models and clinical material; (2) to identify highly promising fellows and junior faculty and mentor them in research areas of Aim 1, in addition to providing them pilot research funds; and (3) to develop educational forums (e.g., a specific course on topics relevant to cardiovascular aging, and an annual symposium) to disseminate key insights that translate basic mechanisms to clinical medicine. Importantly, the Center will leverage infrastructure at the Yale School of Medicine, including the Pepper Center, Center for Clinical Investigation, and Investigative Medicine program. The long-term goals of the Center will be to obtain extramural funding for multi-investigator driven proposals as well as career development faculty grants and an institutional training grant to sustain the training of postdoctoral fellows. In summary, the proposed Center will be a new initiative for Yale and will serve as a beacon of excellence for investigators pursuing research into aging and cardiovascular diseases.

? DESCRIPTION (provided by applicant): Older people suffer from a higher morbidity and mortality from influenza viral lung infections and secondary bacterial pneumonia than younger people. Yet the mechanisms by which aging impairs host defense to respiratory infections are not well understood. Recent human genetic studies have shown that high expression of macrophage migration inhibitory factor (MIF) alleles confer a 50% survival benefit in older individuals with community-acquired pneumonia. In support of this, our preliminary data indicate that aging is associated with reduced MIF within the aging lung in mice. Furthermore, we show that in the lungs, aging and MIF deficiency share several features: increased senescence prior to lung infection, and increased lung damage, and impaired viral clearance after influenza viral lung infection. Importantly, MIF deficiency also worsens outcomes after influenza viral infection followed by S. pneumonia bacterial infection. Here, we will investigate the mechanisms underlying MIF's effects during infectious exacerbations of the aging lung by studying genetically-defined mice infected with two clinically-relevant respiratory models: primary influenza virus, and influenza viral infection followed by S. pneumonia bacterial infection. Aim 1 will investigate mechanisms by which aging and MIF deficiency impair clearance of influenza virus with increased lung damage, with a focus on type I interferon production, an inflammatory mediator that is critical to host defense against viral infection. Aim 2 will investigate the role f MIF in host defense after secondary bacterial infection with aging. Both Aims will test the role of MIF by employing novel MIF transgenic mice and new pharmacological MIF modulators. Therefore, this proposal will yield novel information concerning how the aging lung responds to respiratory pathogens, which could provide novel information to improve therapies for older people who succumb to respiratory infections.

? DESCRIPTION (provided by applicant): Chronic low-level inflammation is a hallmark of aging. However, the mechanistic links between chronic inflammation and cardiovascular diseases are not fully understood. As aging is one of the strongest independent risk factors for atherosclerosis, understanding this link is of critical importance to the clinical care of our ever increasing population of older people. In an experimental model of atherosclerosis (i.e., LDLr -/- mice), we found that aging leads to larger atherosclerotic lesions; increased production of macrophage chemo-attractants, CCL2 and osteopontin; peripheral monocytosis; and an increase in macrophage recruitment into the aorta. Our prior work demonstrates that without atherosclerosis, aged vascular smooth muscle cells (VSMC) contribute to the aortic inflammatory milieu by producing increased CCL2 and osteopontin. Importantly, we showed that the production of these inflammatory molecules depends on MyD88, an innate immune adaptor protein downstream of the Toll like receptors. We also found that aging impairs autophagosome formation within VSMC and is accompanied by increased mitochondrial mass and reactive oxygen species. Taken together, these findings suggest that damaged mitochondria accumulate in aging VSMC due to reduced autophagy, leading in turn to a buildup of mitochondrial components that activate MyD88 to enhance atherosclerosis. To test this hypothesis, we will use a new model system in which MyD88 is selectively and inducibly deleted within VSMC of aging atherosclerotic prone mice to examine the extent by which MyD88 expression within VSMC controls age-enhanced macrophage recruitment into the aorta and atherosclerosis. We will also use mice in which autophagy is disabled within VSMC, to determine if autophagy in VSMC controls basal inflammation, monocyte recruitment into the aorta, and the development of atherosclerosis. Our proposal will yield critical insights into how aging impacts inflammatory responses in VSMC to enhance atherosclerosis. Our findings may contribute to the development of novel therapies for atherosclerosis in the older population.

DESCRIPTION (provided by applicant): Viral infections induce higher morbidity and mortality in older people than in younger individuals. Based on both experimental and clinical studies, this disease burden is thought to be due to declining immune responses. However, our published work supported by the last cycle of the award challenges this paradigm as we found that older mice exhibit dysregulated immune responses during viral infection that induce immune pathology. This dysregulation consists of exaggerated IL-17 responses produced by natural killer T (NKT) cells, innate immune lymphocytes that respond rapidly to pathogens, coupled to defective type I interferon (IFN) responses by plasmacytoid dentritic cells (pDCs), sentinel immune cells that aid viral clearance. This defective viral clearance synergizes with the age-elevated IL-17 responses leading to severe liver inflammation and death. During non-lethal systemic viral infections, exaggerated inflammatory responses (i.e., IL-6 production) by NKT-cells coupled with defective type I IFN responses by pDCs induce an inflammatory environment that skews adaptive immune CD4+ T cells to an IL-17 producing phenotype. We have also observed the age-elevated IL-17 response coupled to defective type I IFNs in other viral infections such as in localized influenza lung infections. Here, we propose to study the underlying cellular and molecular mechanisms for dysregulation of immune responses with aging by using murine models to determine 1) if exaggerated inflammatory responses by NKT cells coupled to defective pDC responses are critical for the generation of IL-17 anti-viral CD4+ T cells during systemic herpes viral infections with aging; and 2) whether exaggerated IL-17 responses by aged NKT cells coupled with impaired type I IFN responses by pDCs also induce immune pathology during influenza viral lung infection. Our work will greatly differ from mainstream research in the field and may lead to novel anti-inflammatory therapies to improve immunity to viral infections with aging.

? DESCRIPTION (provided by applicant): Cardiovascular diseases are posing an increasing threat to the health of older people. However, how aging impacts cardiovascular disease remains unclear. A highly collaborative environment is required to unravel the complexities of this problem. The goal of this leadership award is to develop a world-class center on aging and cardiovascular diseases at Yale School of Medicine to foster highly productive research collaborations and to educate and train the next generation of leaders in this important field. The proposed Center would be the first of its kind in the nation and will be led by Dr. Goldstein, an established physician-scientist and cardiologist who investigates how aging impacts inflammation. The Center's specific goals will be addressed in the following three aims: (1) to bring together established investigators to broadly examine how increased inflammation with aging enhances cardiovascular diseases employing both pre-clinical models and clinical material; (2) to identify highly promising fellows and junior faculty and mentor them in research areas of Aim 1, in addition to providing them pilot research funds; and (3) to develop educational forums (e.g., a specific course on topics relevant to cardiovascular aging, and an annual symposium) to disseminate key insights that translate basic mechanisms to clinical medicine. Importantly, the Center will leverage infrastructure at the Yale School of Medicine, including the Pepper Center, Center for Clinical Investigation, and Investigative Medicine program. The long-term goals of the Center will be to obtain extramural funding for multi-investigator driven proposals as well as career development faculty grants and an institutional training grant to sustain the training of postdoctoral fellows. In summary, the proposed Center will be a new initiative for Yale and will serve as a beacon of excellence for investigators pursuing research into aging and cardiovascular diseases.