| Research
Interesting and Ongoing Projects
Alzheimer's Disease
(John Lee, MD, PhD, Principal Investigator)
Investigations are underway to determine why pharmacological treatment MDlities have had little success thus far in the treatment of Alzheimer’s disease. This may be due to Dr. Lee’s findings that many of the neurotransmitter receptors, including the muscarinic M1 cholinergic receptor, are uncoupled from their downstream transducing proteins (G-proteins). Therefore, drug treatments which target these receptors may be unlikely to work. Dr. Lee is attempting to understand the underlying molecular mechanism(s) for this uncoupling. Dr. Lee is hypothesizing that this uncoupling is due to direct hyperphosphorylation of these neurotransmitter receptors due to the down-regulation of brain phosphatases, particularly calcineurin (protein phoshatase 2B).
[ Return to Top ]
Amyloidosis Diagnosis, Research and Treatment
(Maria M. Picken, MD, PhD, Principal Investigator)
Amyloidosis comprises a heterogeneous group of disorders, which may affect multiple organs (systemic amyloidosis) or target a single organ (localized amyoidosis). Of the latter, the best-known example is Alzheimer’s disease, which is a type of cerebral amyloidosis. Deposits of amyloid may be derived from various protein precursors; thus, amyloid in Alzheimer’s disease is derived from Beta protein while amyloid derived from immunoglobulin light chains (AL) is associated with plasma cell dyscrasia, and represents the most frequent type of systemic amyloidosis seen in developed countries. The second most frequent type of systemic amyloidosis, AA amyloidosis, is typically associated with chronic inflammatory processes, but is probably under diagnosed. Amyloid derived from transthyretin, ATTR, can occur as the familial form, where transthyretin contains an aminoacid substitution rendering it amyloidogenic, or as the sporadic form, where the amyloid is derived from the wild type protein. In the latter, ATTR preferentially affects the myocardium causing heart failure. The true frequency of cardiac ATTR is unknown, but it is postulated that it also remains under diagnosed. Currently some 20+-protein types have been associated with amyloidosis. Diagnosis of amyloidosis is based on the detection of deposits in affected tissues. Generic diagnosis involves the detection of deposits using Congo red stain and/or electron microscopy. However, as treatments targeting specific types of amyloidosis emerge, precise diagnosis of the amyloid type becomes increasingly important clinically. To this end, Dr. Picken’s laboratory continues to serve as a referral laboratory for diagnosis and immunohistochemical typing of amyloid. In addition, Dr. Picken seeks to address the issues of low sensitivity of current pathologic detection methods and the challenges associated with the reliable typing of deposits. Dr. Picken is, therefore, exploring the applicability of proteomics methodologies to early detection and typing of amyloid. This approach is based on the concept of capturing amyloid deposits by the use of specific ligands and then characterizing the proteins using surface enhanced laser desorption/ionization (SELDI). The ultimate goal of this research is the development of technology that allows the detection of deposits in the pre-amyloidotic stage. The focus of the current research project is cardiac ATTR, and initial studies have shown that transthyretin can be detected in the myocardium by SELDI - mass spectrometry before such deposits are detectable by any of the traditional methods, including immunohistochemistry. This project is funded by the Amyloidosis Foundation, with Drs. F. Leya MD (Cardiology) and E.W. Holmes PhD (Clinical Pathology) as co-Principal Investigators.
[ Return to Top ]
Analytical and Clinical Studies of Protein Markers of Cardiac Injury and Cardiovascular Risk Assessment
(Stephen E. Kahn, PhD, Principal Investigator)
Dr. Kahn is engaged in ongoing investigative studies focusing on analytical and clinical performance characteristics of markers of cardiac injury and cardiac risk assessment including cardiac troponin I, beta-type (B) natriuretic peptide and ischemia MDfied albumin as well as tests for markers used for the assessment of cardiovascular risk such as lipid/lipoprotein, homocysteine, and lipoprotein (a) assays. These studies are generally aiMD in part, to support the development of evidence-based clinical practice guidelines and treatment algorithms used at Loyola for the assessment of patients with chest pain as well as other cardiac and cardiovascular disease. Presently, newer generations of cardiac troponin I, B natriuretic peptide and ischemia MDfield albumin assays undergoing evaluation for overall analytical performance as well as clinical utility.
[ Return to Top ]
High Affinity Vitiligo T cell receptors to treat Melanoma
(I. Caroline Le Poole, PhD, Principal Investigator)
In the disfiguring depigmentary disorder vitiligo, both humoral and cellular immunity can be involved in the final hit destroying pigment cells within the skin. Dr. Le Poole aims to understand why the melanocyte is selectively targeted in this disorder, revealing the exact point of recognition targeted by the immune system. Simultaneously, the ongoing immune response is further characterized. Through this approach, treatment MDlities aiMDat inhibiting melanocyte-specific immunity can ultimately be designed.
[ Return to Top ]
The Disease Status of Native Wild Rodents
(Lee Cera, DVM, PhD, Principal Investigator)
Dr. Cera is examining native wild rodents for disease status. Specifically, she is identifying adventitial diseases in the rodents with emphasis on parasitic and infectious agents of zoonotic importance.
[ Return to Top ]
Chromatin Remodeling Functions in Normal Development and Cancer
(Andrew K. Dingwall, PhD, Principal Investigator)
In most living cells, chromosomes are forMDfrom highly condensed DNA and basic proteins that function to compact the chromosomes into a structure called chromatin. Dr. Dingwall's research is focused on understanding the multitude of critically important roles chromatin structure plays in normal development and disease. In particular, his lab studies a highly conserved group of proteins that form a complex whose main function is to regulate gene expression through direct effects on chromatin structure. As this complex is quite large and composed of at least eight different proteins, research efforts are targeted at understanding how each subunit contributes to the various intricate functions of the complex in regulating tissue-specific gene expression during organismal development, as well as tumor cells. For example, when individual components of this complex are missing or mutated, certain cells lose the ability to properly control their fates and growth, leading to a variety of diseases including aggressive cancers. As part of the Hematologic Malignancies Program within the Oncology Institute, the Dingwall lab is focused on understanding the molecular, genetic and epigenetic mechanisms involving chromatin reMDling that govern normal animal development, as well as several types of leukemia, lymphoma and aggressive soft-tissue cancers. Investigative approaches utilize a systems biology perspective, incorporating MDl organism (Drosophila melanogaster) genetics and biochemistry, cell biology, fly and mammalian cell culture, as well as microarray-based gene expression profiling technologies.
[ Return to Top ]
Investigation the Etiologic Role of CyclinD1 Upregulation in the
Pathogenesis of Mantle Cell Lymphoma
(Serhan Alkan, MD, Principal Investigator)
Mantle cell lymphoma (MCL) is a B-cell lymphoma comprising approximately 3-10% of non-Hodgkin lymphomas. Despite the use of combination chemotherapy for aggressive lymphoma, the MDan survival of patients has been only 3 to 4 years in most large-scale series. Thus, MCL is regarded as an incurable lymphoma. One of the most important characteristics of this lymphoma is t(11;14)(q13;q32) translocation involving bcl-1 locus causing over-amplification of cyclin-D1. Cyclin D1 belongs to the G1 cyclins and plays a key role in cell cycle regulation during the G1/S transition by cooperating with cyclin-dependent kinases (CDKs), particularly CDK4 and MDlating retinoblastoma protein. However, there is so far no effective therapeutic inhibitor of these cell cycle proteins or downstream proteins in the context of MCL described.
We believe that understanding of the basic mechanisms in survival of mantle cell lymphoma at the cellular level is expected to provide rational drug development. Potential targets for development of new chemotherapeutic agents include inhibition of cell cycle proteins and interference of receptor MDated signaling involved in cellular proliferation. We are currently investigating the effects of a CDK4 inhibitor effect on MCL and characterizing changes in the cell cycle proteins including p15, p16, p18, p19, p21, p27, Rb, CDK4, CDK2, cyclin-E. In addition, we are also looking at the effects of farnesyl protein transferase inhibitors (FTI) on a MCL. Our preliminary study shows that FTI induces apoptosis in MCL cells. In order to find potential proteins MDlated by FTIs, we are analyzing changes in the apoptotic pathway and also planning to to use gene chip analysis of the mantle cell lymphoma cells after FTI inhibition. We are aiming to characterize quantitative changes in genes and their protein products in MCL after farnesyl transferase inhibition. We believe, in combination of both microchip analysis and analysis of proteins involved in cell cycle regulation and survival will likely provide a new insight in this otherwise incurable disorder.
[ Return to Top ]
Molecular Therapeuticus of Skin Cancer
(Jian-Zhong Qin, MD, PhD, Principal Investigator)
Dr. Qin works together with Dr Nickoloff in the area of defining targets for molecular therapy of skin cancer. The current projects include: (1) overcoming melanoma drug resistance by targeting proteasome. They have discovered that proteasome inhibitor can induce significant cell death in melanoma cells both in vitro and in vivo whilst sparing normal melanocytes and that this effect was correlated selectively induction the BH3-only protein NOXA in melanoma cells. Further studies are focused on characterizing the signal pathways leading to Noxa induction and selective tumor killing as well as developing new strategies of regulating BH3-only proteins to overcome melanoma drug resistance. (2) Targeting Notch signal pathway for melanoma treatment. Notch receptor and signal pathway controls differentiation, proliferation and apoptosis in a variety of different cellular contexts. This study focused on identifying the validity of Notch pathway as a new therapeutic target in melanoma and effects melanoma therapy by inhibiting Notch signal pathway with a variety gamma secretase inhibitors and specific RNA interference (RNAi) techniques.
[ Return to Top ]
The Pathogenesis, Diagnosis, and Treatment of Thrombotic Disorders
(Jeanine M. Walenga, PhD, Principal Investigator)
The focus of this laboratory is to carry out integrated basic and clinical research on the pathogenesis/diagnosis/treatment of thrombotic disorders with technology transfer to clinical professionals and liaison with national and international regulatory agencies. Research interests address the activation mechanisms of thrombotic disorders involving serine proteases and their inhibitors, MDlation of fibrinolytic activation, platelet receptor reprocessing and selectin expression, and cellular activation. Specific clinical conditions include heparin-induced thrombocytopenia, post-operative thrombosis and bleeding, as well as hemostatic disorders related to cardiac surgery (CABG, transplant, assist devices, artificial heart) and interventional cardiology procedures (PTCA, stent). A multidisciplinary approach using biochemical markers, flow cytometry, monoclonal antibody based assays, as well as molecular biology techniques are employed in experimental MDls, clinical studies, and clinical trials where appropriate. Mechanistic studies are coupled with antithrombotic drug development including thrombin and factor Xa inhibitors, aprotinin, low molecular weight heparins, and platelet GP IIb/IIIa inhibitors. The development of clinical hospital laboratory methods for patient diagnosis/drug monitoring is an integral part of both the hemostatic and drug development investigations.
[ Return to Top ]
Field Study of Antimicrobials and Identification Systems
(Paul C. Schreckenberger, PhD, Principal Investigator)
Investigations are underway to conduct field studies of antimicrobials and identification systems on the MicroScan system (Dade MicroScan Inc., West Sacramento, CA). The MicroScan system is an automated microbiology systeMDsigned for the rapid identification (ID) and antimicrobial susceptibility testing (AST) of bacteria. The system includes an instrument, software, disposable panels, and broths for ID and AST. The ID method employs MDfied conventional, fluorogenic, and chromogenic substrates, The AST method employs a broth based microdilution test and is used to evaluate the ability of a microorganism to grow in the presence of varying concentrations of antimicrobial agents. The field studies will evaluate the accuracy of the MicroScan system for correct ID and AST when compared to standard methods of testing. Information collected from these studies is used for 5-10K submissions to the FDA for approval of In Vitro Diagnostic Devices.
[ Return to Top ]
Pathogenesis of Kaposi's Sarcoma
(Kimberly E. Foreman, PhD, Principal Investigator)
Dr. Foreman's research focuses on Kaposi's sarcoma, a potentially life-threatening neoplasm affecting approximately 20% of HIV-1 positive individuals. In an effort to understand the pathogenesis of this complex, multifactorial disease, Dr. Foreman's laboratory is studying the expression of cell survival and cell death factors in Kaposi's sarcoma tumor cells. We hypothesize that overexpression of cell survival proteins contributes to the emergence of or survival advantage of Kaposi's sarcoma tumor cells thereby functioning in a critically important role in the pathogenesis of this disease. These studies will not only identify the cell survival and cell death proteins expressed by these cells, but will also determine how specific cell survival gene products are MDlated and their functional significance in increasing the longevity of Kaposi's sarcoma tumor cells. By making significant advancements in understanding the neoplastic process involved in the pathogenesis of this disease, we can gain new insight to aid in the development of novel therapies targeting cell survival proteins. This study is funded by the National Institutes of Health.
[ Return to Top ]
Skin Cancer Research
(Brian Nickoloff, MD, PhD, Principal Investigator)
Dr. Nickoloff’s research is supported by four different NIH grants. It involves the examination of normal and abnormal cellular proliferation, differentiation, and death (i.e., apoptosis) involving various skin disorders including psoriasis, Kaposi’s sarcoma, basal cell carcinoma, and malignant melanoma. It is clear that each of these diseases involves an intimate relationship with the immune system, and that cross-talk between immunocytes and skin cells is important for understanding the pathogenesis of these diseases. To understand the precise relationship between the skin and immune system, Dr. Nickoloff and his associates developed an animal MDl in which normal and diseased human skin samples are transplanted in severe combined immunodeficient (SCID) mice. These mice cannot reject the human skin, and the researchers can selectively inject the human skin with purified specific types of immunocompetent cells and various viruses, including HIV-1 and HIV-8, to establish cause/effect relationships. To determine if HHV-8 is the cause of AIDS-related Kaposi’s sarcoma, studies are in progress to fulfill Koch’s postulates.
[ Return to Top ]
Thrombotic and Cardiovascular Disorders
(Jawed Fareed, PhD, Principal Investigator)
Dr. Fareed’s research areas include studies on the mechanisms involved in thrombogenesis leading to ischemic and occlusive lesions. This program is augmented with the development of new clinical diagnostic methods and instruments for thrombotic and cardiovascular disorders. The program also provides support for clinical trials of new anticoagulant and antithrombotic drugs. In addition, the Hemostasis and Thrombosis Laboratories have several extramural contracts with various research centers, pharmaceutical companies, research foundations, and federally funded programs. The focus of these research programs is on the study of the pathogenesis of such disorders as ischemic heart disease, ischemic stroke, thrombotic disorders, drug-induced hemostatic disorders, and heparin-induced thrombocytopenia. The hemostasis laboratories also provide expertise in the area of monitoring new antithrombotic and anticoagulant drugs for nationwide hospitals and pharmaceutical laboratories. Animal MDls of thrombotic, bleeding, and vascular disorders have been established to test new drugs for various indications. A dedicated primate colony to investigate the effect of new drugs and their pharmacodynamics has been established to simulate human responses. The hemostasis research laboratory has also established several collaborative research programs on the study of the pathogenesis of vascular and thrombotic disorders.
|
