Frederick D. Goldman, MD
Research Profile

Dr. Goldman’s primary research interests are in the area of bone marrow failure syndromes. These are conditions where the bone marrow is no longer capable of making other red blood cells, white blood cells, or platelets. Many of these conditions are in fact inherited and they can affect infants, young children, and even adults. As an example, Shwachman Diamond Syndrome is a disease where patients have low white blood cell counts and both pancreatic insufficiency. These patients often develop severe bone marrow failure and this is the leading cause of death. We have been studying how white blood cells in this disorder crawl around (chemotaxis) and believe that abnormal chemotaxis is one of the underlying causes for these patients having increased risks of infections. Dr. Goldman collaborates with Dr. Soll who is looking at proteins inside of cells that may contribute to this abnormal white blood cell chemotaxis. When patients with Shwachman Diamond Syndrome develop aplastic anemia or severe bone marrow failure, they are then in need of a bone marrow transplant. Dr. Goldman’s transplant group has developed a protocol that has fewer side effects. Other bone marrow failure syndromes including Dyskeratosis congenita and Fanconi’s anemia are also transplanted with modified less toxic regimens.

Dr. Goldman’s laboratory is also interested in the role of telomeres in the development of blood forming units in the bone marrow as well as cell aging. Various bone marrow syndromes are associated with short telomeres and the focus of his studies are looking to determine whether telomere shortening makes cells more sensitive to chemotherapy. Additionally, Dr. Goldman’s laboratory is currently developing in a gene therapy model with the hope of being able to someday cure certain genetic disorders without the need of a bone marrow transplant.

Finally, Dr. Goldman’s other interests include understanding what causes various sorts of immune deficiencies in children. His laboratory is able to do a number of molecular tests to look for the causes of these immune problems. Finally, his laboratory also looks at how certain drugs affect the immune system and how the immune system recovers after bone marrow transplantation.

Lab Members:

Ike Akabogu, Farzana Pashankar, MD, Vibha Singhal, Dale Winnike

Affiliation:

• Department of Pediatrics
• Division of Hematology/Oncology

Model System:

• Telomere Studies: Our primary model system employs human somatic cells (lymphocytes, hematopoietic stem cells, keratinocytes, fibroblasts) from patients with Dyskeratosis congenita. This condition is due to a defect in the human telomerase RNA molecule, hTERC, resulting in diminished telomerase activity, shortened telomeres, and premature cell senescence. The goals of these studies are to understand the role of telomerase activity in various cellular functions, with the ultimate goal of devising gene therapy strategies as a protective tool for cellular senescence.
• Graft-versus-host disease: We utilize cells isolated from patients enrolled on a Phase III study examining the efficacy of a new drug, plaquenil, to treat chronic graft-versus-host disease. Our in vitro studies exam both the function and phenotype of lymphocytes, and in addition, qualitate immune responses by measuring production of TH1 or TH2 cytokines.
• Human immune deficiencies: Our primary model system utilizes lymphocytes, freshly isolated from patients with various immune disorders. These patients are often initially seen in the Pediatric Immune Disorders Clinic. Studies exam lymphocyte function including production of cytokines, activation of various signal transduction cascades, and apoptosis.

Recent Publications:

1. Stepanovic V, Wessels D, Goldman FD, Geiger J, Soll D. The Chemotaxis Defect of Shwachman-Diamond Syndrome Leukocytes. Cell Motil Cytoskeleton, 2004; Mar; 57(3):158-174
2. Knudson M, Kuklarni S, Ballas Z, Bessler M, Goldman F. Association of Immune Abnormalities with Telomere Shortening in Autosomal Dominant Dyskeratosis Congenita. Blood, 105(2):684-690, 2005.
3. Vibhakar R, Radhi M, Rumelhart S, Tatman D, Goldman F. Successful Unrelated Umbilical Cord Blood Transplantation in Children with Shwachman-Diamond Syndrome. Bone Marrow Transplant. 2005, 36:855-861.
4. Grossman WJ, Radhi M, Schauer D, Gerday E, Grose C, Goldman FD. Development of hemophagocytic lymphohistiocytosis in triplets infected with HHV-8. Blood. 2005 Aug 15; 106(4):1203-6.
5. Grossman WJ, Radhi M, Schauer D, Gerday E, Grose C, Goldman FD. Development of hemophagocytic lymphohistiocytosis in triplets infected with HHV-8. Blood. 2005 Aug 15; 106(4):1203-6.
6. Goldman F, Bouarich R, Kulkarni S, Freeman S, Du H, Harrington L, Mason PJ, Londono-Vallejo A, Bessler, M. The effect of TERC haploinsufficiency on the inheritance of telomere length. Proc Natl Acad Sci. 2005, Nov 22; 102(47):17119-24.
7. Pashankar F, Singhal V, Gatti R, Akabogu I, Goldman F. Intact T Cell Responses in Ataxia Telangiectasia, Clin Immunol, 2006, Aug; 120(2):156-62. [Epub 2006 June 8].
8. Shelton BK, Griffin JM, Goldman FD. IGIV Therapy: Optimizing Care of Patients in the Oncology Setting. Oncol Nurs Forum. 2006, Sep 1; 33(5):911-21.
9. Filipovich AH, Bleesing J, Goldman F. Emerging Targets for Hematopoietic Cell Transplantation (HCT):Genetic Disorders of Hematopoiesis and Immunity. Biol Blood Marrow Transplant, 2007, Jan;13S1:58-63.
10. Radhi M, Rumelhart S, Tatman D, Goldman F. Severe autoimmune hemolytic anemia after unrelated umbilical cord blood transplant for familial hemophagocytic lymphohistiocytosis: significant improvement after treatment with rituximab. J Pediatr Hematol Oncol. 2007, Feb.29 (2):125-7.
11. She K,. Gilman A, Aslanian A, Shimizu H, Krailo M, Chen W, Reid G, Wall D, Goldman F, Schultz K. Altered TLR9 Responses in Circulating B cells at the Onset of Chronic GVHD, Biol Blood Marrow Transplant, 2007 Apr;13(4):386-97. Epub 2007 Feb 15.
12. Westin ER, Chavez E, Lee KM, Gourronc FA, Riley S, Lansdorp PM, Goldman FD, Klingelhutz AJ. Telomere Restoration and Extension of Proliferative Lifespan in Dyskeratosis Congenita Cells. Aging Cell, 2007 Jun;6(3):383-94 Epub 2007 Mar 23
13. Fujii H, Cuvelier G, She K, Aslanian S, Shimizu H, Kariminia A, Krailo M, Chen Z, McMaster R, Goldman F, Grupp SA, Wall DA, Gilman AL, Schultz KR. Biomarkers in Newly Diagnosed Pediatric Extensive Chronic Graft-versus-Host Disease. Blood, 2008 Mar 15; 111(6):3276-85. Epub 2007 Oct 9.
14. Goldman FD, Aubert G, Klingerlhutz AJ, Hills M, Cooper SR, Hamilton WS, Schluter AJ, Eaves CJ, Lansdorp PM. Characterization of Primitive Hematopoietic Cells from Patients with Dyskeratosis Congenita. Blood, 2008 May 1; 111(9):4523-31. Epub 2008 Feb 29.
15. Hong YD, Pumbo E, Ping A, Bagby GC, Maziarz RT, Reiss UM, Chirnomas D, Shimamura A, Vlachos A, Lipton JM, Goyal RK, Goldman F, et al. TERC and TERT Gene Mutations in Patients With Bone Marrow Failure and the Significance of Telomere Length Measurements. Accepted, Blood, 2008.