Howard Gendelman, MD

Professor and Chair, Dept. of Pharmacology & Experimental Neuroscience Larson Professor of Internal Medicine and Infectious Diseases Director, Center for Neurovirology & Neurodegenerative Disorders 985880 Nebraska Medical Center Omaha, NE  68198-5880 Phone:  402.559.8920 Fax: 402.559.3744 hegendel@unmc.edu

Ongoing Projects

1. Studies of the biophysical and effector cell properties of blood-borne macrophages as they regulate leukocyte entry, glial immunity, and neurotoxic activities for HAD. These events are pivotal to viral neuropathogenesis. Clearly, once inside the brain, mononuclear phagocytes (MP) (microglia, parenchymal, and perivascular macrophages) serve as the principal cellular reservoir for HIV and effectors for neurodegeneration. Indeed, following immune activation, MP secrete scores of immune "neurotoxic" factors that damage the blood-brain barrier (BBB) and neuropil. If macrophage chemotaxis, neurotoxicity, and/or transendothelial brain migration could be halted (each or together) nervous system disease would be abrogated. Until now, little attention was paid to the spatial parameters of cell biophysiology, migration, and the mechanisms underlying changes in cell shape and volume. Our investigations are designed to tackle this issue head on by deciphering how ion channels effect macrophage cell volume and cytosolic calcium. The importance of such events cannot be overstated as they regulate the critical components of MP transendothelial migration. The processes that effect MP trafficking are currently being explored, in the context of macrophage differentiation, activation, and viral infection. In particular, we are working to ascertain the exact ionic currents (independently and together), which are sensitive to cell volume, shape, and movement. Technical aspects of the program will include whole-cell and single-channel patch-clamp electrophysiological recording assays. Migration of MP will be performed on cell suspensions through the use of artificial barriers (for example Boyden chemotaxis microchamber assays or a BBB model). Ion channel blockers will assess ways to halt the process of MP migration. To correlate these findings to what could occur in an infected human host, MP migration/invasion is being investigated in organotypic cultures of brain slices and in a SCID mouse model of HIVE. Cell migration is evaluated by scoring dye-stained monocytes under laser confocal microscopy (through serial optic sectioning of human or mouse brain tissue). Ongoing investigations seek to ascertain how MP effector function evolves from primary neurotrophic to neurotoxic activities. We have an integrated proteonomics facility under the direction of Dr. Pawel Ciborowski. We plan to integrate our ongoing research efforts in cell/neural biology with the subsequent discovery of novel proteins. Our intent is to uncover how they are regulated, their effects on viral replication, and their biological role in health and disease within the nervous system. Our works involve differential display, forward phase liquid chromatography (FPLC), and reverse phase high performance liquid chromatography (RP-HPLC) will facilitate these efforts and be part of a collaborative initiative for gene discovery already underway for several years at the CNND. Other investigators involved, in part, for these works include Drs. Tsuneya Ikezu, Anuja Ghorpade, Jialin Zheng and Huangui Xiong.

2. Coordinate drug testing (anti-inflammatory, neuroprotective, and anti-retroviral) in severe combined immunodeficient SCID mice with HIVE. Ongoing efforts are operative in the hopes of designing adjunctive therapeutic strategies for treatment and/or prevention of neurologic disease following HIV-1 infection. In this regard, my laboratory is a projected core facility of the Rochester Cooperative NeuroAIDS Drug Discovery Group (RCNDDG). Promising anti-inflammatory and/or neuroprotective drugs, developed in laboratory assays are being tested for therapeutic efficacy in a SCID mouse model of HIVE. Brain tissue and/or sera are used for measuring drug levels and pathology in the mice. Such works support translational (bench to bedside) researchers efforts and directly effect the performance of clinical trials. The works, in toto, are based on the concept that HAD is, in part, a reversible metabolic encephalopathy caused by defective immunity of virus-infected MP which serve both as reservoirs for productive HIV-1 infection and principal sources of neurotoxic activities within the central nervous system. The development of ways to inhibit toxic inflammatory activities in brain may serve to both ameliorate and prevent complications of persistent viral replication in brain serving as critical adjunctive therapies to ongoing potent anti-retroviral regimens, the principal goals of the RCNDDG. Measurements of drug efficacy include behavioral/cognitive testing, ex vivo electrophysiology, neuropathology, and most importantly the use of quantitative 1H magnetic resonance spectroscopy and spectroscopic imaging (MRS, SI) techniques to monitor biochemical changes in brain. A 7-Tesla magnet was recently purchased for these studies and brain levels of n-acetyl-aspartate, total creatine, choline, and myoinostitol can now be measured in mice infected with HIVE. These studies involve collaborative efforts with Drs. Yuri Persidsky, Michael Boska and Huangui Xiong.

3. Induction of protective immunity and neuroregeneration in animal models of Parkinson's and Alzheimer's disease and HIV-1 associated dementia (vaccine development and testing). Recently, it was discovered that T lymphocyte responses elicited against CNS antigens (for example, myelin basic protein) can evoke a neuroprotective immune response within damaged optic nerves and spinal cord tissues. Interestingly, such neuroprotective strategies can simultaneously elicit experimental autoimmune encephalitis (EAE) in recipient animals. Such works have led to a new field of investigation, coined protective autoimmunity. These results were confirmed in subsequent works utilizing a spinal root avulsion disease model and were the focus of my a sabbatical I undertook late in 2000 in Professor Michal Schwartz's laboratory at the Weizmann Institute. It was hypothesized that activated T-lymphocytes express neurotrophic factors (BDNF, NT-3, or GDNF) or can induce such responses from glia they come in contact with. We are exploring the abilities of the immune competent T lymphocytes to invade the CNS and induce protection against secondary neuronal degeneration. Our ongoing works are focused on developing therapeutic vaccines for neurodegenerative disorders using unique brain antigenic targets. Ongoing efforts are designed to determine how macrophage and T cell mediated neuroprotective responses are induced by such experimental approaches. Simultaneously we are also exploring the mechanisms through which MP secretes neurotrophins. A variety of activation signals are being compared to assess the signaling events that lead to a predominant MP neurotrophic response.

Representative Publications: (total 201):

Shibata, A., Zelivyanskaya, M., Carlson, K.A., Limoges, J., Branecki, C., Bishu, S., Xiong, H., and Gendelman, H.E. Immunoregulation of Human Macrophage Neurotrophic Activities. J. Neuroimmunol. 142:112-129, 2003.

Erichsen, D., Lopez, A.L., Peng, H., Ryan, L., Bauer, M., Williams, C., Morgello, S., Ghorpade, A., Cotter, R.L., Gendelman, H.E. and Zheng, J. Neuronal Fractalkine: regulation of macrophage activation and inflammatory factor production during HIV-1 associated dementia. J. Neuroimmunol. 138(1-2):144-155, 2003.

Suryadevara, R., Holter, S., Borgmann, K., Persidsky, R., Labenz, C., Persidsky, Y., Gendelman, H.E., Wu, L., Ghorpade, A. Regulation of Tissue Inhibitor of Metalloproteinase-1 by Astrocytes: Links to HIV-1 dementia. Glia 44(1)47-56, 2003.

Luo, X., Carlson, K.A., Wonja, V., Mayo, R., Biskup, T., Stoner, J., Anderson, J., Gendelman, H.E., and Melendez, L.M. Macrophage proteomic fingerprinting predicts HIV-1 associated cognitive impairment. Neurology 60(12):1931-7, 2003.

Xiong, H., McCabe, L., Skifter, D., Monaghan, D., and Gendelman, H.E. Activation of NR1a/NR2B Receptors by Monocyte-Derived Macrophage Secretory Products: Implications for HIV-1-Associated Dementia. Neurosci. Letters, 341:246-250, 2003.

Dou, H., Luo, X., Boska, M.D., Faraci, J., Birusingh, K., Gelbard, H., and Gendelman, H.E. Sodium Valproate protects neurons during HIV-1 encephalitis: therapeutic development in a murine model of human disease. J. Neurosci, 23(27): 000-000, 2003.

Carlson, K., Leisman, G., Limoges, J., Masliah, E. Gendelman, H.E., and Ikezu T. OTK18: A Novel Macrophage Transcriptional Suppressive Factor Linked to HIV-1 Encephalitis. In press, J. Immunol. 2003.

Boska, M.D., Mosley, R.L., Nawab, M., Nelson, J.A., Zelivyanskaya, M., Poluetkova, L., Uberti, M., Dou, H., and Gendelman, H.E. Advances in neuroimaging for HIV-1 associated neurological dysfunction: Clues to the diagnosis, pathogenesis and therapy. Current HIV Res. In press, 2003.

EDITED BOOKS AND MONOGRAPHS:

1. Gendelman, H.E., Lipton, S.A., Epstein, L.G., and Swindells, S.: The Neurology of AIDS, Chapman and Hall Publishers, New York, 1997, pp. 1-599.
2. Gendelman, H.E., Innate and Acquired Immunity in Neurodegenerative Disorders, J. Leuk. Biol. (monograph), April 1999.
3. Gendelman, H.E., Rappaport, J., and Hickey, W. The Blood Brain Barrier. J. NeuroVirol. (monograph), December 1999.
4. Gendelman, H.E., Neural Immunity, J. NeuroVirol., December 2002.
5. Gendelman, H.E., Grant, I., Lipton, S.A., Everall, I., and Swindells, S., The Neurology of AIDS second edition. Oxford University Press, London, 2003, in press.